Chalcone derivatives and their use to treat diseases

ABSTRACT

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula  
                 
or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application.

This patent application claims priority to U.S. Provisional PatentApplication Ser. No. 60/342,034 filed Dec. 19, 2001 and U.S. ProvisionalPatent Application Ser. No. 60/386,482 filed Jun. 5, 2002.

The present invention is in the field of novel chalcone derivatives,pharmaceutical compositions and methods for treating a variety ofdiseases and disorders, including inflammation and cardiovasculardisease.

BACKGROUND OF THE INVENTION

Adhesion of leukocytes to the endothelium represents a fundamental,early event in a wide variety of inflammatory conditions, autoimmunedisorders and bacterial and viral infections. Leukocyte recruitment toendothelium is mediated in part by the inducible expression of adhesionmolecules on the surface of endothelial cells that interact withcounterreceptors on immune cells. Endothelial cells determine whichtypes of leukocytes are recruited by selectively expressing specificadhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1),intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 bindsto the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages,eosinophils, and basophils but not neutrophils. This interactionfacilitates the firm adhesion of these leukocytes to the endothelium.VCAM-1 is an inducible gene that is not expressed, or expressed at verylow levels, in normal tissues. VCAM-1 is upregulated in a number ofinflammatory diseases, including arthritis (including rheumatoidarthritis), asthma, dermatitis, psoriasis, cystic fibrosis, posttransplantation late and chronic solid organ rejection, multiplesclerosis, systemic lupus erythematosis, inflammatory bowel diseases,autoimmnune diabetes, diabetic retinopathy, rhinitis,ischemia-reperfusion injury, post-angioplasty restenosis, chronicobstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, conjunctivitis, atherosclerosis,coronary artery disease, angina and small artery disease.

Coronary heart disease (CHD), primarily as a result of atherosclerosis,remains the leading cause of death in industrialized countries.Atherosclerosis is a disease characterized by vascular inflammation,deposition of lipids in the arterial vessel wall and smooth muscle cellproliferation resulting in a narrowing of the vessel passages. Inadvanced stages of the disease atherosclerotic lesions can becomeunstable resulting in plaque rupture, thrombosis, myocardial infarctionand ischemic heart disease. It is now well accepted that the initiatingevents in atherosclerosis are local injury to the arterial endotheliumthat results in the induction of VCAM-1 and recruitment of mononuclearleukocytes that express the integrin counterreceptor, VLA-4, (O'Brien,et al., J. Clin. Invest., 92: 945-951, 1993). Subsequent conversion ofleukocytes to foamy macrophages results in the synthesis of a widevariety of inflammatory cytokines, growth factors, and chemoattractantsthat help propagate formation of the mature atheromatous plaque byfurther inducing endothelial activation, leukocyte recruitment, smoothmuscle cell proliferation, and extracellular matrix deposition.Pharmacological inhibition of VCAM-1 expression has been shown toinhibit atherosclerosis in several animal models (Sundell et al.,Circulation, 100: 42, 1999). A monoclonal antibody against VCAM-1 hasalso been shown to inhibit neointimal formation in a mouse model ofarterial wall injury (Oguchi, S., et al., Arterioscler. Thromb. Vasc.Biol., 20: 1729-1736, 2000).

Asthma, which is increasing in prevalence and morbidity world-wide, is achronic inflammatory disease characterized by lung eosinophilia andbronchial hyperreactivity. The interaction between VCAM-1 on lungendothelial cells and VLA-4, which is the integrin counterreceptorexpressed on eosinophils, is thought to be important for selectiveeosinophil recruitment. Eosinophils have been considered an importanteffector cell in the pathogenesis of asthma and other allergic diseases.Activated eosinophils release proteins such as major basic protein (MBP)that have been demonstrated to induce bronchial hyperreactivity, one ofthe defining criteria of asthma (Bousquot, et al., N. Engl. J. Med.,323: 1033-1039, 1990). It has been demonstrated that VCAM-1 is markedlyupregulated on human bronchial vascular endothelium of subjects withasthma who have air flow limitation, when compared with subjects withoutasthma (Pilewski, et al., Am. J. Respir. Cell Mol. Biol., 12, 1-3, 1995;Ohkawara, Y., et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12, 1995;Gosset, P., et al., Int. Arch. Allergy Immunol. 106: 69-77, 1995;Hacken, N. H., et al., Clin. Exp. Allergy, 28 (12): 1518-1525, 1998). Anelevation in serum soluble VCAM-1 levels has also been demonstrated inpatients undergoing a bronchial asthma attack compared with levels understable conditions (Montefort, S., Koizumi, A., Clin. Exp. Immunol., 101:468-73, 1995). Several animal studies further demonstrate a spatial andtemporal association between VCAM-1 and asthma. In a mouse model ofallergic asthma, VCAM-1 expression was shown to be induced by allergenchallenge, and administration of an anti-VCAM-1 antibody was effectivein inhibiting eosinophil infiltration that occurred in this model(Metzger, W. J., et al., J. Allergy Clin. Immunol., 93: 183, 1994).Further evidence for the importance of VCAM-1 in allergic asthma comesfrom work in IL-12 knockout mice. IL-12 knockout mice had fewereosinophils and VCAM-1 expression than wildtype mice; however,administration of recombinant IL-12 at the time of ova sensitization andchallenge restored lung VCAM-1 expression and eosinophilia (Wang, S., etal., J. Immunol., 166:2741-2749, 2001). There are several examples whereblocking the integrin receptors for VCAM-1 have had positive effects onanimal models of asthma (Rabb et al., Am. J. Respir. Care Med. 149:1186-1191, 1994; Abraham, W, et al., Am. J. Respir. Crit. Care Med. 156:696-703. 1997) further demonstrating the importance of VCAM-1/VLA-4interactions in allergic inflammation. Eosinophils are also importanteffector cells in allergic rhinitis. VCAM-1 has been demonstrated to beupregulated 24 hrs after nasal allergen provocation in patients withseasonal allergic rhinitis but not in normal subjects (Braunstahl, G.J., et al., J. Allergy Clin. Immunol., 107: 469-476, 2001).

Rheumatoid arthritis (RA) is a clinical syndrome of unknown causecharacterized by symmetric, polyarticular inflammation of synovial-linedjoints. The role of adhesion molecules in the pathogenesis of RA hasalso been well documented, and VCAM-1 expression on synovial fibroblastsis a clinical hallmark of RA (Li, P., et al., J. Immunol. 164: 5990-7,2000). VLA-4/VCAM-1 interactions may be the predominant mechanism forrecruitment of leukocytes to the synovium (Dinther-Janssen, et al., J.Immunol. 147: 4207-4210, 1991; Issekeutz and Issekeutz, Clin. Immunol.Immunopathol. 61:436-447, 1991; Morales-Ducret et al., J. Immunol.149:1424-1431, 1992; Postigo et al., J. Clin. Invest. 89:1445-1452,1992; Matsuyama, T., et al, Hum. Cell, 9: 187-192, 1996). In support ofthis, increased VCAM-1 expression has been found in RA synovial tissuecompared with osteoarthritis and control tissue (Wilkinson et al., Lab.Invest. 69:82-88, 1993; Furuzawa-Carballeda, J., et al., Scand. J.Immunol. 50: 215-222; 1999). Soluble VCAM-1 is higher in RA patientsthan in control subjects (Kolopp-Sarda, M. N., et al., Clin. Exp.Rheumatol. 19: 165-70, 2001). Soluble VCAM-1 has been shown to bechemotactic for T cells (Kitani, A., et al., J. Immun. 161: 4931-8,1998), and in addition to being a possible diagnostic marker for RA, maycontribute to its pathogenesis by inducing migration and recruitment ofT cells. VCAM-1 expressed on fibroblast-like synoviocytes has also beenimplicated in enhanced survival of activated synovial fluid B cells(Marinova, Mutafcheia, L., Arthritis Rheum. 43: 638-644, 2000) that mayfurther contribute to RA pathogenesis.

Chronic inflammation and accompanying vascular complications and organdamage characterize systemic lupus erythematosis (SLE). Recent studiessuggest that VCAM-1 plays a role in SLE. Expression of VCAM-1 isincreased on dermal vessel endothelial cells in patients with activesystematic lupus erythematosus (Jones, S. M., British J Dermatol. 135:678-686, 1996) and correlates with increased disease severity (Belmontet al., Arthritis Rheum. 37:376-383, 1994). SLE muscle samples withperivascular infiltrate have greater endothelial cell expression ofVCAM-1 compared with SLE patients without a perivascular infiltrate orwith control samples (Pallis et al., Ann. Rheum. Dis. 52:667-671, 1993).Increased expression of VCAM-1 has also been demonstrated in kidneys oflupus-prone MRL/lpr mice compared to nonautoimmune strains and itsexpression increased with disease severity (McHale, J. F., et al., J.Immunol. 163: 3993-4000, 1999). VCAM-1 expression on mesangial cells invitro can be stimulated by IL-1, TNF-α, and INFγ exposure as well as byanti-endothelial cell IgG fraction and anti-DNA autoantibodies from SLEpatients (Wuthrich, Kidney Int. 42: 903-914, 1992; Papa, N. D., et al.,Lupus, 8: 423-429, 1999; Lai, K. N., et al., Clin Immunol Immunopathol,81: 229-238, 1996). Furthermore, soluble VCAM-1 is higher in SLEpatients than in normal subjects (Mrowka, C., et al., Clin. Nephrol. 43:288-296, 1995; Baraczka, K., et al., Acta. Neurol. Scand 99: 95-99,1999; Kaplanski; G.; et al., Arthritis Rheumol. 43: 55-64, 2000; Ikeda,Y., Lupus, 7: 347-354, 1998) and correlates with disease activity(Scudla, V., Vnitr. Lek, 43: 307-311, 1997).

Increased VCAM-1 expression has also been demonstrated in solid organtransplant rejection. Acute transplant rejection occurs when thetransplant recipient recognizes the grafted organ as “non-self” andmounts an immune response characterized by massive infiltration ofimmune cells, edema, and hemorrage that result in the death of thetransplanted organ. Acute rejection occurs in a matter of hours or daysand has been correlated with increased levels of VCAM-1 in tissues andin plasma (Tanio et al., Circulation, 89:1760-1768, 1994; Cosimi et al.,J. Immunol. 144: 4604-4612, 1990; Pelletier, R., et al.,Transplantation, 55: 315, 1992). A monoclonal antibody to VCAM-1 hasbeen shown to inhibit cardiac allograft rejection in mice (Pelletier,R., J. Immunol., 149: 2473-2481, 1992; Pelletier, R., et al.,Transplantation Proceedings, 25: 839-841, 1993; Orosz, C. G., et al., J.Heart and Lung Transplantation, 16: 889-904, 1997) and when given for 20days can cause complete inhibition of rejection and long-term graftacceptance (Orosz C. G., et al., Transplantation, 56: 453-460, 1993).Chronic graft rejection also known as allograft vasculopathy is distinctfrom acute transplant rejection and is a leading cause of late graftloss after renal and heart transplantation. Histologically it ischaracterized by concentric neointimal growth within vessels that islargely due to smooth muscle migration and proliferation. It is thoughtto be the result of endothelial damage brought about by several factorsincluding: ischemia-reperfusion injury, immune complexes, hypertension,hyperlipidemia and viruses. All of these factors have been associatedwith induction of VCAM-1 in endothelial cells. There is also a strongcorrelation of soluble and tissue VCAM-1 levels with chronic rejection(Boratynska, M., Pol. Arch. Med. Wewn, 100: 410-410, 1998; Zembala, M.,et al., Ann. Transplant. 2: 16-9, 1998; Solez K., et al., KidneyInternational., 51: 1476-1480, 1997; Koskinen P. K., et al.,Circulation, 95: 191-6, 1997).

Multiple sclerosis is a common demyelinating disorder of the centralnervous system, causing patches of sclerosis (plaques) in the brain andspinal cord. It occurs in young adults and has protean clinicalmanifestations. It is well documented that VCAM-1 is expressed on brainmicrovascular endothelial cells in active lesions of multiple sclerosis(Lee S. J., et al., J. Neuroimmunol, 98: 77-88, 1998). Experimentaltherapy of experimental autoimmune encephalomyelitis, which is an animalmodel for multiple sclerosis, using antibodies against several adhesionmolecules, including VCAM-1, clearly shows that adhesion molecules arecritical for the pathogenesis of the disease (Benveniste et al., J.Neuroimmunol. 98:77-88, 1999). A time and dose dependent expression ofVCAM-1 and release of soluble VCAM-1 were detected in cultures of humancerebral endothelial cells induced by TNFα, but not in peripheral bloodmononuclear cells (Kallmann et al., Brain, 123:687-697, 2000). Clinicaldata also show that adhesion molecules in blood and cerebrospinal fluidare up-regulated throughout the clinical spectrum of multiple sclerosis(Baraczka, K., et al., Acta. Neurol. Scand. 99: 95-99, 1999; Reickmann,P., et al., Mult. Scler., 4: 178-182, 1998; Frigerio, S., et al., J.Neuroimmunol, 87: 88-93, 1998) supporting the notion that therapieswhich interfere with cell adhesion molecules such as VCAM-1 may bebeneficial in modifying this disease (Elovaara et al., Arch. Neurol.57:546-551, 2000).

Diabetes mellitus is a metabolic disease in which carbohydrateutilization is reduced and that of lipid and protein is enhanced.Evidence has accumulated that increased levels of adhesion molecules mayplay a functional pathophysiological role in diabetes (Wagner and Jilma,Hormone and Metabolic Research, 29: 627-630, 1997; Kado, S., DiabetesRes. Clin. Pract., 46: 143-8, 1999). It is caused by an absolute orrelative deficiency of insulin and is characterized by chronichyperglycemia, glycosuria, water and electrolyte loss, ketoacidosis, andcoma. Elevated circulating adhesion molecules including VCAM-1 have beendetected in patients with diabetes and in experimental models ofdiabetes in animals (Lorini et al., Hormone Research, 48: 153, 1997;Otsuki et al., Diabetologia, 40: A440, 1997; Hart et al., FASEB J.11:A340, 1997; Albertini et al., Diabetologia, 39: A240, 1996; Wagner etal., Diabetologia, 39: A205, 1996; Enghofer et al., Diabetologia, 39:A97, 1996; Koga M., Diabet. Med., 15: 661-667, 1998). In addition,complications of diabetes often include peripheral vasculopathies suchas diabetic retinopathy and diabetic nephropathy. It is believed thatadhesion of leukocytes to the peripheral vasculature plays a centralrole in the vasculopathies often associated with diabetes.

Crohn's disease, also known as regional enteritis, is a subacute chronicinflammatory condition of unknown cause, involving the internal ileumand less frequently other parts of the gastrointestinal tract. It ischaracterized by patchy deep ulcers that may cause fistulas, andnarrowing and thickening of the bowel by fibrosis and lymphocyticinfiltration. Ulcerative colitis is a chronic disease of unknown causecharacterized by ulceration of the colon and rectum, with rectalbleeding, mucosal crypt abscesses, inflammatory pseudopolyps, abdominalpain, and diarrhea. It has been reported that serum VCAM-1 reflects thegrade of intestinal inflammation in patients with Crohn's disease orulcerative colitis (Jones, et al., Gut, 36: 724-30, 1995; Goggins etal., Gastroenterology, 108: A825, 1995; Goeke and Manns,Gastroenterology, 106: A689, 1994; Goeke et al., J. Gasterokenterol.32:480-486, 1997; Loftus et al., Gastroenterology, 108: A684, 1995;Tahami et al., Gastroenterology, 118: A344, 2000). Antibodies to VCAM-1have been shown to ameliorate experimentally-induced colitis in mice(Soriano, A., Lab. Invest. 80: 1541-1551, 2000).

Psoriasis is a chronic skin disease characterized by erythematousscaling plaques as a result of keratinocyte hyperplasia, influx ofimmune cells and endothelial activation (Nickoloff, B. J., et al., J.Invest. Dermatol., 127: 871-884, 1991). VCAM-1 is upregulated inpsoriatic skin as compared to normal skin (Groves, R. W., J. Am. Acad.Dermatol., 29: 67-72, 1993; Uyemura, K., et al., J. Invest. Dermatol.101: 701-705, 1993) and levels of circulating VCAM-1 correlate withdisease activity (Schopf, R. E., Br. J. Dermatol., 128: 34-7, 1993).

U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231,and 5,773,209 to Medford, et al., as well as the corresponding WO95/30415 to Emory University indicate that polyunsaturated fatty acids(“PUFAs”) and their hydroperoxides (“ox-PUFAs”), which are importantcomponents of oxidatively modified low density lipoprotein (LDL), inducethe expression of VCAM-1, but not intracellular adhesion molecule-1(ICAM-1) or E-selectin in human aortic endothelial cells, through amechanism that is not mediated by cytokines or other noncytokinesignals. This is a fundamental discovery of an important and previouslyunknown biological pathway in VCAM-1 mediated immune responses. Asnon-limiting examples, linoleic acid, linolenic acid, arachidonic acid,linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide(15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1or E-selectin. Saturated fatty acids (such as stearic acid) andmonounsaturated fatty acids (such as oleic acid) do not induce theexpression of VCAM-1, ICAM-1 or E-selectin.

WO 98/51662, filed by AtheroGenics, Inc. and listing as inventorsRussell M. Medford Patricia K. Somers, Lee K. Hoong, and Charles Q.Meng, claims priority to provisional application U.S. Ser. No.60/047,020, filed on May 14, 1997. This application discloses the use ofa broad group of compounds as cardiovascular protectants that exhibit atleast one, and sometimes a composite profile, of reducing cholesterol,lowering LDL, and inhibiting the expression of VCAM-1.

U.S. Pat. No. 5,155,250 to Parker, et al. discloses that2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The samecompounds are disclosed as serum cholesterol lowering agents in PCTPublication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat. No.5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenolsinhibit the peroxidation of LDL, lower plasma cholesterol, and inhibitthe expression of VCAM-1, and thus are useful in the treatment ofatherosclerosis.

WO 98/51289, which claims priority to provisional application U.S. Ser.No. 60/047,020, filed on May 14, 1997 by Emory University listing PattySomers as sole inventor, discloses the use of a group of compounds ascardiovascular protectants and antiinflammatory agents which exhibit atleast one, and sometimes a composite profile, of reducing cholesterol,lowering LDL, and inhibiting the expression of VCAM-1 and thus can beused as antiinflammatory and cardivascular treating agents.

U.S. Pat. Nos. 5,380,747; 5,792,787; 5,783,596; 5,750,351; 5,821,260;5,807,884; 5,811,449; 5,846,959; 5,877,203; and 5,773,209 to Medford, etal., teach the use of dithiocarbamates of the general formula A-SC(S)-Bfor the treatment of cardiovascular and other inflammatory diseases.Examples include sodium pyrrolidine-N-carbodithioate, tri-sodiumN,N-di(carboxymethyl)-N-carbodithioate, and sodiumN,N-diethyl-N-carbodithioate. The patents teach that the compoundsinhibit the expression of VCAM-1.

WO 98/23581 discloses the use of benzamidoaldehydes and their use ascysteine protease inhibitors.

WO 97/12613 of Comicelli et al. discloses compounds for the inhibitionof 15-lipogenase to treat and prevent inflammation or atherosclerosis.Compounds disclosed include benzopyranoindole, benzimidazdle,catacholes, benzoxadiazines, benzo[a]phenothiazine, or related compoundsthereof.

Japanese Patent No. 06092950 to Masahiko et al. discloses preparation ofepoxy compounds wherein electron deficient olefins such as acylstyrenederivatives, styrene derivatives, and cyclohexenone derivatives areefficiently oxidized by a hydrogen peroxide derivative in the presenceof a primary or secondary amine in an organic solvent to give saidepoxides which are useful intermediates for pharmaceutical and flavoringmaterials.

U.S. Pat. No. 5,217,999 to Levitzki et al. discloses substituted styrenecompound as a method of inhibiting cell proliferation.

Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are naturalproducts related to flavonoids. WO 99/00114 (PCT/DK98/00283) disclosesthe use of certain chalcones, 1,3-bis-aromatic-propan-1-ones(dihydrochalcones), and 1,3-bisaromatic-prop2-yn-1-ones for thepreparation of pharmaceutical compositions for the treatment ofprophylaxis of a number of serious diseases including i) conditionsrelating to harmful effects of inflammatory cytokines, ii) conditionsinvolving infection by Helicobacter species, iii) conditions involvinginfections by viruses, iv) neoplastic disorders, and v) conditionscaused by microorganisms or parasites.

WO 00/47554 filed by Cor Therapeutics describes a broad class ofsubstituted unsaturated compounds for use as antithrombotic agents.

WO 96/20936 (PCT/KR95/00183) discloses thiazolidin-4-one derivatives ofthe formula:

which act as PAF antagonists or 5-lipoxygenase inhibitors. The compoundsare used in the prevention and treatment of inflammatory and allergicdisorders mediated by platelet-activating factor and/or leukotrienes.

U.S. Pat. No. 4,085,135 discloses 2′-(carboxymethoxy)-chalcones withantigastric and antiduodenal ulcer activities.

U.S. Pat. No. 5,744,614 to Merkle et al. discloses a process forpreparing 3,5-diarylpyrazoles and various derivatives thereof byreacting hydrazine hydrate with 1,3-diarylpropenone in the presence ofsulfuric acid and an iodine compound.

U.S. Pat. No. 5,951,541 to Wehlage et al. discloses the use of salts ofaromatic hydroxy compounds, such as (hydroxyaryl)alkenone salts, asbrighteners in aqueous acidic electroplating baths. In addition theinvention discloses that such compounds have a lower vapor pressure thanthe known brighteners, as a single substance and in the electroplatingbaths, in order to avoid losses of substance. They also have high watersolubility properties.

Japanese Patent No. 07330814 to Shigeki et al. disclosesbenzylacetophenone compounds as photoinitiator compounds.

Japanese Patent No. 04217621 to Tomomi discloses siloxane chalconederivatives in sunscreens.

U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a process forpreparation of 2′-(carboxymethoxy)-chalcones having antigastric and antiduodenal activities with low toxicity and high absorptive ratio in thebody. This patent suggests that the high absorptive ratio in the body isdue to the 2′-carboxymethoxy group attached to the chalcone derivative.

U.S. Pat. No. 4,855,438 discloses the process for preparation ofoptically active 2-hydroxyethylazole derivatives which have fungicidaland plant growth-regulating action by reacting an α-β-unsaturated ketonewhich could include a chalcone or a chalcone derivative with anenantiomerically pure oxathiolane in the presence of a strongly basicorganometallic compound and at temperatures ranging from −80 to 120° C.

European Patent No 307762 assigned to Hofmann-La Roche disclosessubstituted phenyl chalcones.

E. Bakhite et al. in J. Chem. Tech. Biotech. 1992, 55, 157-161, havedisclosed a process for the preparation of some phenyloxazolederivatives of chalcone by condensing 5-(p-acetylphenyl)-2-phenyloxazolewith aromatic aldehydes.

Herencia, et al., in Synthesis and Anti-inflammatory Activity ofChalcone Derivatives, Bioorganic & Medicinal Chemistry Letters 8 (1998)1169-1174, discloses certain chalcone derivatives with anti-inflammatoryactivity.

Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J.Pharm. Pharmacol. 2000, 52; 163-171 describes that certain chalconeshave potent antiinflammatory activity.

Zwaagstra, et al., Synthesis and Structure-Activity Relationships ofCarboxylated Chalcones: A Novel Series of CysLT₁ (LT₄) ReceptorAntagonists; J. Med. Chem., 1997, 40, 1075-1089 discloses that in aseries of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and4-[2-(2-quinolinyl)ethenyl]-substituted, 2′, 3′, 4′, or 5′ carboxylatedchalcones, certain compounds are CysLT₁ receptor antagonists.

JP 63010720 to Nippon Kayaku Co., LTD discloses that chalconederivatives of the following formula (wherein R¹ and R² are hydrogen oralkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can beused in treating allergies.

JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloseschalcones of the following structure as 5-lipoxygenase inhibitors,wherein R is acyl and R¹-R⁵ are hydrogen, lower alkyl, lower alkoxy orhalo, and specifically that in which R is acyl and R¹-R⁵ are hydrogen.

U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses heterocyclicring-containing chalcones of the following formula as antiallergicagents, wherein A represents a substituted or unsubstituted phenylgroup, a substituted or unsubstituted naphthyl group, or a group:

in which X represents a hydrogen or halogen atom or a hydroxyl, loweralkyl or lower alkoxyl group and B represents —CH═CH—, —N(R⁶)—, R⁶ is alower alkyl group or a lower alkoxyalkyl group, —O— or —S—; W represents—CH═CH— or —CH₂O—, and R₁₋₅ is the same or different and eachindependently represent a hydrogen or halogen atom, a hydroxyl, a loweralkyl, lower alkoxyl, carboxyl, cyano, alkyloxycarbonyl or tetrazolylgroup, a group —CONHR₇ in which R₇ represents a hydrogen atom or a loweralkyl group, or a group —O(CH₂)_(n) R₈ in which R₈ represents acarboxyl, alkyloxycarbonyl or tetrazolyl group and n is from 1 to 4,with the proviso that at least one of the groups R₁₋₅ represents acarboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, the group —CONHR₇or the group —O(CH₂)nR₈; or a salt or solvate thereof.

Reported bioactivies of chalcones have been reviewed by Dimmock, et al.,in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6,1125-1149; Liu et al., Antimalarial Alkoxylated and HydroxylatedChalones: Structure-Activity Relationship Analysis, J. Med. Chem. 2001,44, 4443-4452; Herencia et al, Novel Anit-inflammatory ChalconeDerivatives Inhibit the Induction of Nitric Oxide Synthase andCyclooxygenase-2 in Mouse Peritoneal Macrophages, FEBS Letters, 1999,453, 129-134; and Hsieh et al., Synthesis and Anti-inflammatory Effectof Chalcones and Related Compounds, Pharmaceutical Research, 1998, Vol.15, No. 1, 39-46.

Given that VCAM-1 is a mediator of chronic inflammatory disorders, it isa goal of the present work to identify new compounds, compositions andmethods that can inhibit the expression of VCAM-1. A more general goalis to identify selective compounds and methods for suppressing theexpression of redox sensitive genes or activating redox sensitive genesthat are suppressed. An even more general goal is to identify selectivecompounds, pharmaceutical compositions and methods of using thecompounds for the treatment of inflammatory diseases.

It is therefore an object of the present invention to provide newcompounds for the treatment of disorders mediated by VCAM-1.

It is also an object to provide new pharmaceutical compositions for thetreatment of diseases and disorders mediated by the expression ofVCAM-1.

It is a further object of the invention to provide compounds,compositions, and methods of treating disorders and diseases mediated byVCAM-1, including cardiovascular and inflammatory diseases.

Another object of the invention is to provide compounds, compositions,and method of treating cardiovascular and inflammatory diseases.

It is another object of the invention to provide compounds, compositionsand methods to treat arthritis.

Another object of the invention is to provide compounds, compositionsand methods to treat rheumatoid arthritis. The inventions compounds,compositions and methods are also suitable as disease modifyinganti-rheumatoid arthritis drugs (DMARDs).

It is yet another object of the invention to provide compounds,compositions and methods to treat asthma.

It is another object of the invention to provide compounds, methods andcompositions to inhibit the progression of atherosclerosis.

It is still another object of the invention to provide compounds,compositions, and methods to treat or prevent transplant rejection.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of lupus.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of inflammatory boweldisease.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of autoimmune diabetes.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of multiple sclerosis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of diabetic retinopathy.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of diabetic nephropathy.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of diabetic vasculopathy.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of rhinitis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of ischemia-reperfusioninjury.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of post-angioplastyrestenosis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of chronic obstructivepulmonary disease (COPD).

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of glomerulonephritis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of Graves disease.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of gastrointestinalallergies.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of conjunctivitis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of dermatitis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of psoriasis.

SUMMARY OF THE INVENTION

It has been discovered that particular chalcone derivatives inhibit theexpression of VCAM-1, and thus can be used to treat a patient with adisorder mediated by VCAM-1. Examples of inflammatory disorders that aremediated by VCAM-1 include, but are not limited to arthritis, asthma,dermatitis, cystic fibrosis, post transplantation late and chronic solidorgan rejection, multiple sclerosis, systemic lupus erythematosis,inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy,diabetic nephropathy, diabetic vasculopathy, rhinitis,ischemia-reperfusion injury, post-angioplasty restenosis, chronicobstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, conjunctivitis, atherosclerosis,coronary artery disease, angina and small artery disease.

The compounds disclosed herein can also be used in the treatment ofinflammatory skin diseases that are mediated by VCAM-1, as well as humanendothelial disorders that are mediated by VCAM-1, which include, butare not limited to psoriasis, dermatitis, including eczematousdermatitis, Kaposi's sarcoma, multiple sclerosis, as well asproliferative disorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can beselected to treat anti-inflammatory conditions that are mediated bymononuclear leucocytes.

In one embodiment, the compounds of the present invention are selectedfor the prevention or treatment of tissue or organ transplant rejection.Treatment and prevention of organ or tissue transplant rejectionincludes, but is not limited to treatment of recipients of heart, lung,combined heart-lung, liver, kidney, pancreatic, skin, spleen, smallbowel, or corneal transplants. The compounds can also be used in theprevention or treatment of graft-versus-host disease, such as sometimesoccurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are usefulin both the primary and adjunctive medical treatment of cardiovasculardisease. The compounds are used in primary treatment of, for example,coronary disease states including atherosclerosis, post-angioplastyrestenosis, coronary artery diseases and angina The compounds can beadministered to treat small vessel disease that is not treatable bysurgery or angioplasty, or other vessel disease in which surgery is notan option. The compounds can also be used to stabilize patients prior torevascularization therapy.

Compounds of the present invention are of the formula

or its pharmaceutically acceptable salt or ester, wherein thesubstituents are defined herein.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that compounds of the invention inhibit theexpression of VCAM-1, and thus can be used to treat a patient with adisorder mediated by VCAM-1. These compounds can be administered to ahost as monotherapy, or if desired, in combination with another compoundof the invention or another biologically active agent, as described inmore detail below.

In a 1st embodiment, the invention is represented by Formula I

or its pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α, R) ^(6α), R^(2β), R^(3α), R^(4β),R^(5β and R) ^(6β) are independently selected from the group consistingof hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β), or one ofR^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl; and/or

wherein when one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) is acarbon-carbon linked heterocyclic or heteroaryl, only one of R^(2α),R^(3α), R^(4α), R^(05α) or R^(6α) can be —OCH₃; and/or

wherein when one of R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) is acarbon-carbon linked heterocyclic or heteroaryl, only one of R^(2β),R^(3β), R^(4β), R^(5β) or R^(6β) can be —OCH₃; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo;and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2α), R^(3α), R^(4α), R^(5α), R^(6α) or one of R^(2β),R^(3β), R^(4β), R^(5β), R^(6β) must be selected from the groupconsisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷RR, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR², —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 2^(nd) embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²), —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β), or one ofR^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl; and/or

wherein when one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) is acarbon-carbon linked heterocyclic or heteroaryl, only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; and/or

wherein when one of R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) is acarbon-carbon linked heterocyclic or heteroaryl, only one of R^(2β),R^(3β), R^(4β), R^(5β) or R^(6β) can be —OCH₃; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo;and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2α), R^(3α), R^(4α), or one of R^(2β), R^(3β), R^(4β)must be selected from the group consisting of cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR²,—C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R²,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,

SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 3^(rd) embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)NR²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo;and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β)B, R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2α), R^(3α), R^(4α), R^(5α), or R^(6α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH,—CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R², SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 4th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NR₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²), —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the group“consisting: of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2α), R^(3α), or R^(4α) must be selected from thegroup consisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR₂, —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 5th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle; cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²), —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R¹²);

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂—SO₂NHC(O)NHR₂,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)C(O)OH,—NHC(R¹)C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 6th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²) 2, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)NH₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷RS,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(CH₃)₂C(O)OH, (CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5,or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 7th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²),—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₁₃C(O)OH, and —CH₂)_(y)C(O)OH, wherein y is 1, 2,3, 4, 5, or 6, all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

-   R¹ is independently selected from the group consisting of hydrogen,    lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,    heteroarylalkyl, and heterocyclicalkyl, wherein all may be    optionally substituted by one or more selected from the group    consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl,    hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, oxo,    cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and    —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(CH₃)₂C(O)OH, (CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5,or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂.

In an 8th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R⁶β are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, cycloalkyloxy,cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, dialkylamino, cycloalkylamino,arylamino, aralkylamino, heteroarylamino, heteroaralkylamino,heterocyclicamino, heterocyclicalkylamino, —NHR², N(R²)₂, —NR⁷R⁸,—N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, and —CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,all of which can be optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α)R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(CH₃)₂C(O)OH, (CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5,or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸,and —C(O)N(R²)₂.

In a 9^(th) embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic,heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl,alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,dialkylamino, N(R²)₂, —NR⁷R⁸, tetrazol-5-yl, carboxy, —C(O)OR²,—C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted byone or more selected from the group consisting of halo, alkyl, loweralkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,wherein all may be substituted by one or more selected from the groupconsisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 8-memberedmonocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of tetrazol-5-yl, carboxy, —C(O)OR²,—C(CH₃)₂C(O)OH, (CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 10th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy, —C(O)OR²,—C(O)N(R²)₂, and —C(O)NR⁷R⁸, all of which can be optionally substitutedby one or more selected from the group consisting of halo, alkyl, loweralkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, andlower alkyl, wherein all may be substituted by one or more selected fromthe group consisting of halo, lower alkyl, —NR⁷R⁵, alkoxy, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to7-membered monocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from carboxy or —C(O)OR²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In an 11th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic,

lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy,heterocyclic lower alkoxy, and carboxy, all of which can be optionallysubstituted by one or more selected from the group consisting ofhydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 12th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 13th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl, loweralkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, andheterocyclic lower alkoxy, all of which can be optionally substituted byone or more selected from the group consisting of hydroxy, hydroxyalkyl,—NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²);

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheteroaryl;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 14th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen, fluorine, chlorine, methoxy,ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-1-morpholino)ethoxy,CH₃O(CH₂)₂O(CH₂)₂—,

wherein one of R^(4β), R^(5β) or R^(6β) must be selected from the groupconsisting of thiophen-s-yl, thiophen-3-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol-2-yl, pyrrol-3-yl,1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl,N-Boc-indol-3-yl, N-Boc-pyrrol-2′yl, and N-Boc-pyrrol-3-yl;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 15th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen, methoxy, 3-(1-morpholino)propoxy,2-(1-morpholino)ethoxy, and CH₃O(CH₂)₂O(CH₂)₂;

wherein one of R^(4β), R^(5β) or R^(6β) must be selected from the groupconsisting of thiophen-s-yl, benzo[b]thiophen-2-yl, indol-2-yl,1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol-2′yl, andN-Boc-pyrrol-3-yl;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 16^(th) embodiment, the invention is selected from a compound Acompound selected from the group consisting of

-   4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic    acid;-   4-[3E-(4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3E-(4-Thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)acryloyl]-benzoic acid;-   2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic    acid, sodium salt;-   4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid, sodium    salt;-   4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid;-   4-[3-(2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoic    acid;-   4-[3E-(4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-{4-Fluoro-3-(thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid;-   4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic    Acid;-   4-[3E-2-Fluoro-4-thiophen-2-yl-phenyl)acryloyl]-benzoic acid;-   4-[3E-(2,4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-{3E-[5-(3,5-Dimethyl-isoxazol    4-y)-2,4dimethoxy-phenyl]-acryloyl}-benzoic acid;-   4-[3E-(4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   2-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-indole-1-carboxylic    acid tert-butyl ester;-   4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)acryloyl]-benzoic acid;-   4-{3E-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic    acid;-   4-[3E-(2,4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-{3E-[2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic    acid;-   4-[³E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3E-(3-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-(2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3E-(2,4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-{3E-[4-(1-Carboxy-1-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid;-   2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic    acid;-   4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid;-   5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl-thiophene-2-carboxylic    acid methyl ester;-   5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic    acid;-   4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-(2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic    acid, sodium salt;-   2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1-carboxylic    acid tert-butyl ester;-   4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-{3E-[2-1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid;-   4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid, hydrochloride;-   2 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic    acid;-   4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid;-   4-[3E-(2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid;-   4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid, hydrochloride;-   4-{3E-[4-Methoxy-2-3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid, hydrochloride;-   4-[3E-(2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-[3E-4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoic    acid;-   4-(3E-[5-(1H-Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic    acid;-   4-[3E-2-Carbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic    acid;-   4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl)}-benzoic    acid;-   4-(3E-{4-Methoxy-2-[2-1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic    acid, hydrochloride;-   4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic    acid;-   4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic    acid;-   4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic    acid;-   2-{4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-methyl-propionic    acid;-   4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic    acid, hydrochloride;-   4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic    acid;-   4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzoic    acid; and-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)acryloyl]-benzoic    acid ethyl ester, or its pharmaceutically acceptable salt or ester.

In a 17^(th) embodiment, the invention is a compound selected from thegroup consisting of

-   4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic    acid;-   4-[3E-2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;-   4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic    Acid; and-   4-{3E-[4-Methoxy-2-(2-morpholin-4-y-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic    acid, hydrochloride, or its pharmaceutically acceptable salt or    ester.

In an 18th embodiment, the invention is

-   4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic    acid    or its pharmaceutically acceptable salt or ester.

In a 19^(th) embodiment, the invention is4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid, orits pharmaceutically acceptable salt or ester.

In a 20^(th) embodiment, the invention is4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicAcid; and, or its pharmaceutically acceptable salt or ester.

In a 21st embodiment, the invention is4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride, or its pharmaceutically acceptable salt or ester.

In a 22^(nd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 23rd embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedtetrahydrofurn-2-yl or dihydrofuran-2-yl;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.

In a 24th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl,hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, cycloalkyloxy,cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino,cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²)₂, —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 25th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, and —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², and—C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 26th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, cycloalkyloxy,cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, dialkylamino, cycloalkylamino,arylamino, aralkylamino, heteroarylamino, heteroaralkylamino,heterocyclicamino, heterocyclicalkylamino, —NHR², N(R²)₂, —NR⁷R⁸,—N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl, —C(O)OR²,—C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R²,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, and —C(CH₃)₂C(O)OH,—(CH₂)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²);

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², and—C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸,and —C(O)N(R²)₂.

In a 27th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic,heterocyclic lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy,heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,heterocyclic lower alkoxy, dialkylamino, N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R²,—C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, and —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, lower alkyl,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 8-memberedmonocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², and —C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 28^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —N(R²)C(O)R², —C(O)NH₂,and —C(O)NHR², all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, andlower alkyl which may be optionally substituted by one or more selectedfrom the group consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, heteroaryl, and heterocyclic, wherein all maybe substituted by one or more selected from the group consisting ofhalo, lower alkyl, —NR⁷R⁸, alkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to7-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR₂,—C(O)NHC(O)R², and —C(O)NHSO₂R²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, heterocyclic, amino, aminoalkyl, and —NR⁷R⁸.

In a 29th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, —N(R²)C(O)R², —C(O)NH₂, and —C(O)NHR², all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂;

R¹ is hydrogen;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR²,—C(O)NHC(O)R², and —C(O)NHSO₂R²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of heterocyclic,amino, aminoalkyl, and —NR⁷R⁸.

In a 30th embodiment, the invention is represented by the followingcompounds:

-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-(2-morpholin-4-yl-ethyl)-benzamide;-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-(2,2,2-trifluoro-ethyl)-benzamide;-   4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzamide;-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide;-   4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzamide;-   N-Acetyl-4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)acryloyl]-benzamide;    and-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl-benzamide.

In a 31^(st) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR²,—OC(R¹)₂C(O)N(R¹)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of thiol, —SC(R¹)₂C(O)OH,—SC(R¹)₂C(O)OR², —SCH₂C(O)OH, SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂,SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂,—SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 32nd embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁹ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R⁴ must beselected from the group consisting of thiol, —SC(R¹)₂C(O)OH,—SC(R¹)₂C(O)OR², —SCH₂C(O)OH, SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂,SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂,—SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 33^(rd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl loweralkyl, heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl,polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²), —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂, —SC(R¹)₂C(O)OH,—SC(R¹)₂C(O)OR², —SCH₂C(O)OH—SO₂NH₂, SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,cyano, tetrazol-5-yl, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, arylarylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, —SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²) 2, —SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸,and C(O)N(R²)₂.

In a 34th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl loweralkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino loweralkyl,

hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy,heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,heterocyclic lower alkoxy, dialkylamino, N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R²,—SCH₂C(O)OH —SO₂NH₂, —SO₂NHR², —SO₂N(R²)₂, SO₂N(R²)₂, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²) 2, —SO₂NHC(O)NR⁷R⁸, —C(O)N(R²)₂,—C(O)NR⁷R⁸, and —C(O)NHSO₂R², all of which can be optionally substitutedby one or more selected from the group consisting of halo, alkyl, loweralkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, lower alkyl,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R¹)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,wherein all may be substituted by one or more selected from the groupconsisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 8-memberedmonocyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 35th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, alkenyl, alkynyl, carbocycle,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl,

hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy,heterocyclic lower —N(R²)C(O)R², —SCH₂C(O)OH —SO₂NH₂, —SO₂NHR₂,—SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, and —C(O)NHSO₂R², all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen andlower alkyl, which may be optionally substituted by one or more selectedfrom the group consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl andlower alkyl, which may be substituted by one or more selected from thegroup consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to7-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, and —SO₂NHC(O)R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 36^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, alkenyl, alkynyl, carbocycle, heteroaryl,heterocyclic, hydroxyl, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,heteroaryl lower alkoxy, heterocyclic lower alkoxy, —N(R²)C(O)R²,—SO₂NH₂, —SO₂NHR₂, SO₂NHC(O)R², —SR₂, SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂,—SO₂NHC(O)NR⁷R⁸, and —C(O)NHSO₂R², all of which can be optionallysubstituted by one or more selected from the group consisting ofalkenyl, acyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, —NR⁷R⁸, alkoxy,oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is hydrogen;

R² is lower;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —SC(R¹)₂C(O)OR², —SO₂NH₂,—SO₂NR⁷R⁸, and —SO₂NHC(O)R².

In a 37^(th) embodiment, the invention is represented by the followingcompound:

-   4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzenesulfonamide;-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4dimethoxy-phenyl)-acryloyl]-benzenesulfonamide;-   4-{3E-[4Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;-   2-{5-Methoxy-2-[3-oxo-3-(4-sulfamoyl-phenyl)-E-propenyl]-4-thiophen-2-yl-phenoxy}-2-methyl-propionic    acid;-   2-{2,4-Dimethoxy-5-[3-oxo-3-(4-sulfamoyl-phenyl)-E-propenyl]-phenyl}-indole-1-carboxylic    acid tert-butyl ester;-   4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-y-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;-   4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl-benzenesulfonamide;-   4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide,    hydrochloride;-   4-{3E-[4-Methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;-   4-[3E-(2,4-Dimethoxy-5-pyridin-3-yl-phenyl)-acryloyl]-benzenesulfonamide;-   4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[2-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;-   4-{3E-[2-(Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;    and-   4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzenesulfonamide.

In a 38th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸,

amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino,heterocyclicalkylamino, —NHR², N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,

thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R³, and—C(O)N(R²);

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α)R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 39^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloakyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,—NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl optionally substituted by alkoxycarbonyl.

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of amino, —N(C(O)NHR²)₂, NR²SO₂R² and—NR²SO₂R²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 40th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 41st embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, all ofwhich can be optionally substituted by one or more selected from thegroup consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl,hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is hydrogen or lower alkyl optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃;

with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from —OC(R¹)₂C(O)OH;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 42^(nd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and<C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂,

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R⁴ and R^(5β) taken together form aheterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo;and/or

At least one of R^(2α), R^(3α), or R^(4α) must be selected from thegroup consisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R², —OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino; aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 43^(nd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently alkyl or lower alkyl;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,linked together forming a 6-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃; and/or

R^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken together, orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a heterocyclic ring optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.

In a 44^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)N—HSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃; and/or

R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2α), R^(3α), or R^(4α) must be selected from thegroup consisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, S(2NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)N⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂,

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 45^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy,

all of which can be optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R² is independently alkyl or lower alkyl;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,linked together forming a 6-membered monocyclic ring;

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) can be —OCH₃; and/or

R^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5-membered ring containing one nitrogen, which may optionally besubstituted with one or more selected from the group consisting ofalkyl, lower alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,alkoxycarbonyl; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂COOH.

In a 46th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²k, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4 to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α), or one ofR^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedheterocyclic or heteroaryl; and/or

wherein when one of R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) is acarbon-carbon linked heterocyclic or heteroaryl, only one of R^(2β),R^(3β), R^(4β), R^(5β) or R^(6β) can be —OCH₃; and/or

wherein when one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) is acarbon-carbon linked heterocyclic or heteroaryl, only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; and/or

R^(2β) and R^(3β) taken together or R^(3β) and R^(4β) taken together orR^(4β) and R^(5β) taken together, or R^(2α) and R^(3α) taken together orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo;and/or

R^(2β) and R^(3β) taken together or R^(3β) and R^(4β) taken together orR^(4β) and R^(5β) taken together or R^(2α) and R^(3α) taken together orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2β), R^(3β), R^(4β), R^(5β), R^(6β),R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2β), R^(3β), R^(4β), or one of R^(2α), R^(3α), R^(4α)must be selected from the group consisting of cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR²,—C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R²,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)C(O)N(R¹)₂,OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 47th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are inden selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²)₂, —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(2α), R^(3α), R^(4α), R⁵α or R^(6α) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2β),R^(3β), R^(4β), R^(5β) or R^(6β) can be —OCH₃;

with the proviso that R^(2β) and R^(3β) taken together or R^(3β) andR^(4β) taken together or R^(4β) and R^(5β) taken together, or R^(2α) andR^(3α) taken together or R^(3α) and R^(4α) taken together or R^(4α) andR^(5α) taken together form a heterocyclic or heteroaryl optionallysubstituted by one or more alkoxycarbonylalkyl, carboxyalkyl,hydroxyalkyl or aminoalkyl and optionally substituted with one or moreselected from the group consisting of hydroxy, alkyl, carboxy,hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl,oxo, —NR⁷R⁸, and halo; or

R^(2β) and R^(3β) taken together or R^(3β) and R^(4β) taken together orR^(4β) and R^(5β) taken together or R^(2α) and R^(3α) taken together orR^(3α′) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2β), R^(3β), R^(4β), R^(5β), R^(6β),R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) cannot be —OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^(2β), R^(3β), R^(4β), R^(5β), orR^(6β) must be selected from the group consisting of cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4,5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²), SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 48th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²), —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that R^(2β) and R^(3β) taken together or R^(3β) andR^(4β) taken together or R^(4β) and R^(5β) taken together, or R^(2α) andR^(3α) taken together or R^(3α) and R^(4α) taken together or R^(4α) andR^(5α) taken together form a heterocyclic or heteroaryl optionallysubstituted by one or more alkoxycarbonylalkyl, carboxyalkyl,hydroxyalkyl or aminoalkyl and optionally substituted with one or moreselected from the group consisting of hydroxy, alkyl, carboxy,hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl,oxo, —NR⁷R⁸, and halo; or

R^(2β) and R^(3β) taken together or R^(3β) and R^(4β) taken together orR^(4β) and R^(5β) taken together or R^(2α) and R^(3α) taken together orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)²; provided that R^(2β), R^(3β), R^(4β), R^(5β), R^(6β),R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) cannot be —OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH,—CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 49th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂, thiol, alkylthio,cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio,aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio,heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate,sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —C(O)OR²,—C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R²,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —PO₂H₂, —PO₃H₂,—P(R²)O₂H, and phosphate, all of which can be optionally substituted byone or more selected from the group consisting of halo, alkyl, loweralkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃₂C(O)OH,4CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)C(O)NR⁷R⁸,amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR²,—NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R²,—NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, and—NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 50th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²), —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)N)C(O)N(R²), —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4 to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(CH₃)₂C(O)OH, (CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5,or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 51st embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy;lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and —CH₂)_(y)C(O)OH, wherein y is 1, 2,3, 4, 5, or 6, all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(CH₃)₂C(O)OH, (CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5,or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In an 52^(nd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, polyol-alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, cycloalkyloxy,cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, dialkylamino, cycloalkylamino,arylamino, aralkylamino, heteroarylamino, heteroaralkylamino,heterocyclicamino, heterocyclicalkylamino, —NHR², N(R²)₂, —NR⁷R⁸,—N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R⁷R⁸, —SR₂,—SO₂NHC(O)NR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)N², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²), —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,all of which can be optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5,or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸,and —C(O)N(R²)₂.

In a 53^(rd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic,heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl,alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,dialkylamino, N(R²)₂, —NR⁷R⁸, tetrazol-5-yl, carboxy, —C(O)OR²,—C(O)N(R²k, —C(O)NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted byone or more selected from the group consisting of halo, alkyl, loweralkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,wherein all may be substituted by one or more selected from the groupconsisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 8-memberedmonocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of tetrazol-5-yl, carboxy, —C(O)OR²,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 54th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy, —C(O)OR²,—C(O)N(R²)₂, and —C(O)NR⁷R⁸, all of which can be optionally substitutedby one or more selected from the group consisting of halo, alkyl, loweralkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR⁷R⁸,—C(O)NR⁷R⁸, and C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, andlower alkyl, wherein all may be substituted by one or more selected fromthe group consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to7-membered monocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from carboxy or —C(O)OR²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 55th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic,

lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy,heterocyclic lower alkoxy, and carboxy, all of which can be optionallysubstituted by one or more selected from the group consisting ofhydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

In a 56th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), and R^(6β) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

In a 57th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), and R^(6β) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl, loweralkoxy, —O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, andheterocyclic lower alkoxy, all of which can be optionally substituted byone or more selected from the group consisting of hydroxy, hydroxyalkyl,—NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheteroaryl;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

In a 58th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), and R^(6β) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) are independently selectedfrom the group consisting of hydrogen, fluorine, chlorine, methoxy,ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy,CH₃O(CH₂)₂O(CH₂)₂—,

and

wherein one of R^(4α), R^(5α) or R^(6α) must be selected from the groupconsisting of thiophen-s-yl, thiophen-3-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol-2-yl, pyrrol-3-yl,1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl,N-Boc-indol-3-yl, N-Boc-pyrrol-2′yl, and N-Boc-pyrrol-3-yl;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

In a 59th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) are independently selectedfrom the group consisting of hydrogen, methoxy, 3-(1-morpholino)propoxy,2-(1-morpholino)ethoxy, and CH₃O(CH₂)₂O(CH₂)₂;

wherein one of R^(4α), R^(5α) or R^(6α) must be selected from the groupconsisting of thiophen-s-yl, benzo[b]thiophen-2-yl, indol-2-yl,1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol-2′yl, andN-Boc-pyrrol-3-yl;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

In a 60th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), and R^(6β) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

In a 23rd embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), and R^(6β) are independently selectedfrom the group consisting of hydrogen and carboxy;

R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) are independently selectedfrom the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl; heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedtetrahydrofurn-2-yl or dihydrofuran-2-yl;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must becarboxy.

Embodiment 6c. Amide Branch

In a 61st embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂.

In a 62nd embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino-NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, and —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², and—C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 63^(rd) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy,—O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, cycloalkyloxy,cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, dialkylamino, cycloalkylamino,arylamino, aralkylamino, heteroarylamino, heteroaralkylamino,heterocyclicamino, heterocyclicalkylamino, —NHR², N(R²)₂, —NR⁷R⁸,—N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R³, cyano, tetrazol-5-yl, —C(O)OR²,—C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R²,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, and —C(CH₃)₂C(O)OH,—CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², and—C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸,and —C(O)N(R²)₂.

In a 64th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic,heterocyclic lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy,heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,heterocyclic lower alkoxy, dialkylamino, N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R²,—C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, and —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, lower alkyl,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 8-memberedmonocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², and —C(O)NHSO₂R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 65^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —N(R²)C(O)R², —C(O)NH₂,and —C(O)NHR², all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, andlower alkyl which may be optionally substituted by one or more selectedfrom the group consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, heteroaryl, and heterocyclic, wherein all maybe substituted by one or more selected from the group consisting ofhalo, lower alkyl, —NR⁷R⁸, alkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to7-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR²,—C(O)NHC(O)R², and —C(O)NHSO₂R²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, loweralkyl, heterocyclic, amino, aminoalkyl, and —NR⁷R⁸.

In a 66th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, —N(R²)C(O)R², —C(O)NH₂, and —C(O)NHR², all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²2;

R¹ is hydrogen;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4α), R^(5α), or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —C(O)NH₂, —C(O)NHR²,—C(O)NHC(O)R², and —C(O)NHSO₂R²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of heterocyclic,amino, aminoalkyl, and —NR⁷R⁸.

In a 67th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷ R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of thiol, —SC(R¹)₂C(O)OH,—SC(R¹)₂C(O)OR², —SCH₂C(O)OH, SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂,SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂,—SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 68th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R²,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of thiol, —SC(R¹)₂C(O)OH,—SC(R¹)₂C(O)OR², —SCH₂C(O)OH, SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂,SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂,—SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 69th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl loweralkyl, heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl,polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic-lower alkoxy,—OC(R¹)C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂, —SC(R¹)₂C(O)OH,—SC(R¹)₂C(O)OR², —SCH₂C(O)OH —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,cyano, tetrazol-5-yl, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, arylarylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸,and —C(O)N(R²)₂.

In a 70th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl loweralkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino loweralkyl, hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy,heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,heterocyclic lower alkoxy, dialkylamino, N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R²,—SCH₂C(O)OH —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —C(O)N(R²)₂,—C(O)NR⁷R⁸, and —C(O)NHSO₂R², all of which can be optionally substitutedby one or more selected from the group consisting of halo, alkyl, loweralkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, lower alkyl,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,wherein all may be substituted by one or more selected from the groupconsisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 8-memberedmonocyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 71st embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, alkenyl, alkynyl, carbocycle,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl,

hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy,heterocyclic lower alkoxy, —N(R²)C(O)R², —SCH₂C(O)OH —SO₂NH₂, —SO₂NHR₂,—SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, and —C(O)NHSO₂R², all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen andlower alkyl, which may be optionally substituted by one or more selectedfrom the group consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy,—C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl andlower alkyl, which may be substituted by one or more selected from thegroup consisting of halo, lower alkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to7-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or R^(6α) l must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, and —SO₂NHC(O)R²;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 72nd embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, alkenyl, alkynyl, carbocycle, heteroaryl,heterocyclic, hydroxyl, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,heteroaryl lower alkoxy, heterocyclic lower alkoxy, —NR²)C(O)R²,—SO₂NH₂, —SO₂NHR₂, SO₂NHC(O)R², —SR₂, SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂,—SO₂NHC(O)NR⁷R⁸, and —C(O)NHSO₂R², all of which can be optionallysubstituted by one or more selected from the group consisting ofalkenyl, acyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, —NR⁷R⁸, alkoxy,oxo, cyano, —C(O)NR⁷R⁸, and C(O)N(R²)₂;

R¹ is hydrogen;

R² is lower;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —SC(R¹)₂C(O)OR², —SO₂NH₂,—SO₂NR⁷R⁸, and —SO₂NHC(O)R².

In a 73rd embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)C(O)NR⁷R⁸,

amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino,aralkylamino, heteroaryl amino, heteroaralkylamino, heterocyclicamino,heterocyclicalkylamino, NHR², N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)C(O)OR², —NHC(O)R², N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,

thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²), SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂,

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 74^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, all of which can be optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl optionally substituted by alkoxycarbonyl.

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of amino, —N(C(O)NHR²)₂, NR²SO₂R² and—NR²SO₂R²;

wherein all R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 75th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²k, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NR₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸ alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from the group consisting of —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)C(O)NH₂, OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸; alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 76th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β)R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α) andR^(6α) are independently selected from the group consisting of hydrogen,halogen, heteroaryl, heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, all of which canbe optionally substituted by one or more selected from the groupconsisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl,hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl; —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R¹ is hydrogen or lower alkyl optionally substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R² is lower alkyl optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a6-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃;

with the proviso that at least one of R^(2β), R^(3β), or R^(4β) must beselected from —OC(R¹)₂C(O)OH;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 77th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂NR²,—NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸,—NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio,haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²);

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R⁾₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5α) or R^(6β) can be —OCH₃; and/or

R^(2β) and R^(3β) taken together or R^(3β) and R^(4β) taken together orR^(4β) and R^(5β) taken together, or R^(2α) and R^(3α) taken together orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo;and/or

at least one of R^(2β), R^(3β), or R^(4β) must be selected from thegroup consisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²), SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 78th embodiment, the invention is represented by Formula I or itspharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy,

all of which can be optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R² is independently alkyl or lower alkyl;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,linked together forming a 6-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃; and/or

R^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken together, orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a heterocyclic ring optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.

In a 79^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, aryl amino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy,lower alkoxy, —C(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene,cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OR,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen,lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, loweralkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl,heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, whereinall may be substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,alkenyl and aryl and linked together forming a 4- to 12-memberedmonocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be —OCH₃; and/or

R^(2β) and R^(3β) taken together or R^(3β) and R^(4β) taken together orR^(4β) and R^(5β) taken together or R^(2α) and R^(3α) taken together orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2β), R^(3β), R^(4β), R^(5β), R^(6β),R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) cannot be —OC(R¹)₂C(O)OH;and/or

at least one of R^(2β), R^(3β), or R^(4β) must be selected from thegroup consisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂,

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substitutedwith one or more selected from the group consisting of halo, alkyl,lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.

In a 80^(th) embodiment, the invention is represented by Formula I orits pharmaceutically acceptable salt or ester, wherein:

R^(2β), R^(3β), R^(4β), R^(5β), R^(6β), R^(2α), R^(3α), R^(4α), R^(5α)and R^(6α) are independently selected from the group consisting ofhydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy,

all of which can be optionally substituted by one or more selected fromthe group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸,alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸,and —C(O)N(R²)₂;

R² is independently alkyl or lower alkyl;

R⁷ and R⁸ are independently selected from the group consisting of alkyl,linked together forming a 6-membered monocyclic ring;

wherein one of R^(4α), R^(5α) or R^(6α) must be a carbon-carbon linkedheterocyclic or heteroaryl, and only one of R^(2β), R^(3β), R^(4β),R^(5β) or R^(6β) can be OCH₃; and/or

R^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken together orR^(3α) and R^(4α) taken together or R^(4α) and R^(5α) taken togetherform a 5-membered ring containing one nitrogen, which may optionally besubstituted with one or more selected from the group consisting ofalkyl, lower alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,alkoxycarbonyl; provided that R^(2β), R^(3β), R^(4β), R^(5β), R^(6β),R^(2α), R^(3α), R^(4α), R^(5α) and R^(6α) cannot be —OC(R¹)₂COOH.

As an 81^(st) embodiment, the invention is a pharmaceutical compositioncoprising any of the above 80 embodiments or any of the specificExamples below together with one or more pharmaceutically acceptablecarriers.

An 82^(nd) embodiment includes embodiments 1-80 above or any of theExamples as a means to treat or prophylactically treat an inflammatorydisorder including arthritis, rheumatoid arthritis, asthma, diabeticretinopathy, diabetic nephropathy, diabetic vasculopathy, multiplesclerosis, allergic rhinitis, chronic obstructive pulmonary disease,systemic lupus erthematosus, atherosclerosis, and restinosis.

A further embodiment includes the intermediates used to make the finalcompounds of the invention. Said intermediates are useful as startingmaterials for making the compounds of the invention as well as havingpharmaceutical activity alone.

Another embodiment of the invention includes the process for making boththe intermediates as well as the final compounds.

Definitions

A wavy line used as a bond “

”, denotes a bond which can be either the E- or Z-geometric isomer.

When not used as a bond, the wavy line indicates the point of attachmentof the particular substituent.

The terms “alkyl” or “alk”, alone or in combination, unless otherwisespecified, refers to a saturated straight or branched primary,secondary, or tertiary hydrocarbon from 1 to 10 carbon atoms, including,but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and sec-butyl,. The term “lower alkyl” alone or in combinationrefers to an alkyl having from 1 to 4 carbon atoms. The alkyl group may,be optionally substituted with any moiety that does not otherwiseinterfere with the reaction or that provides an improvement in theprocess, including but not limited to but limited to halo, haloalkyl,hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxylderivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl,sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl,phosphoryl, phosphine, thioester, thioether, acid halide, anhydride,oxime, hydrozine, carbamate, phosphonic acid, phosphonate, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in Greene et al., Protective Groups inOrganic Synthesis, John Wiley & Sons, Second Edition, 1991, herebyincorporated by reference. Specifically included are CF₃ and CH₂CF₃.

The term “alkenyl”, alone or in combination, means a non-cyclic alkyl of2 to 10 carbon atoms having one or more unsaturated carbon-carbon bonds.The alkenyl group may be optionally substituted with any moiety thatdoes not otherwise interfere with the reaction or that provides animprovement in the process, including but not limited to but limited tohalo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido,carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl,sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl,phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide,anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate,either unprotected; or protected as necessary, as known to those skilledin the art, for example, as taught in Greene et al., Protective Groupsin Organic Synthesis, John Wiley & Sons, Second Edition, 1991, herebyincorporated by reference. Specifically included are CF₃ and CH₂CF₃.

The term “alkynyl”, alone or in combination, means a non-cyclic alkyl of2 to 10 carbon atoms having one or more triple carbon-carbon bonds,including but not limited to ethynyl and propynyl. The alkynyl group maybe optionally substituted with any moiety that does not otherwiseinterfere with the reaction or that provides an improvement in theprocess, including but not limited to but limited to halo, haloalkyl,hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxylderivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl,sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl,phosphoryl, phosphine, thioester, thioether, acid halide, anhydride,oxime, hydrozine, carbamate, phosphonic acid, phosphonate, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in Greene et al., Protective Groups inOrganic Synthesis, John Wiley & Sons, Second Edition, 1991, herebyincorporated by reference. Specifically included are CF₃ and CH₂CF₃.

The terms “carboxy”, “COOH” and “C(O)OH” are used interchangeably.

The terms “alkoxycarbonyl” and “carboalkoxy” are used interchangeably.Used alone or in combination, the terms mean refer to the radical—C(O)OR, wherein R is alkyl as defined herein.

The term “thio”, alone or in combination, means the radical —S—.

The term “thiol”, alone or in combination, means the radical —SH.

The term “hydroxy”, alone or in combination means the radical —H.

The term “sulfonyl”, alone or in combination means the radical —S(O)₂—.

The term “oxo” refers to an oxygen attached by a double bond (═O).

The term “carbocycle”, alone or in combination, means any stable 3- to7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic ortricyclic or an up to 26membered polycyclic carbon ring, any of whichmay be saturated, partially unsaturated, or aromatic. Examples of suchcarbocyles include, but are not limited to, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, ortetrahydronaphthyl (tetralin).

The term “cycloalkyl”, alone or in combination, means a saturated orpartially unsaturated cyclic alkyl, having from 1 to 10 carbon atoms,including but not limited to mono- or bi-cyclic ring systems such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, and cyclohexyl.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The “aryl” groupcan be optionally substituted with one or more of the moieties selectedfrom the group consisting of alkyl, alkenyl, alkynyl, heteroaryl,heterocyclic, carbocycle, alkoxy, oxo, aryloxy, arylalkoxy, cycloalkyl,tetrazolyl, heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid,amino acid esters, amino acid amides, alditol, halogen, haloalkylthi,haloalkoxy, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,aminoalkyl, aminoacyl, amido, alkylamino, dialkylamino, arylamino,nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonate, sulfonyl,alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, haloalkylsulfonyl,sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide,phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime,hydrazine, carbamate, phosphonic acid, phosphate, phosphonate,phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide orany other desired functional group that does not inhibit thepharmacological activity of this compound, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., “Protective Groups in OrganicSynthesis,” John Wiley and Sons, Second Edition, 1999. In addition,adjacent groups on an “aryl” ring may combine to form a 5- to 7-memberedsaturated or partially unsaturated carbocyclic, aryl, heteroaryl orheterocyclic ring, which in turn may be substituted as above.

The term “heterocyclic”, alone or in combination, refers to anonaromatic cyclic group that may be partially (containing at least onedouble bond) or fully saturated and wherein the ring contains at leastone heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus.The terms “heteroaryl” or “heteroaromatic”, alone or in combination,refer to an aromatic ring containing at least one heteroatom selectedfrom sulfur, oxygen, nitrogen or phosphorus. The heteroaryl orheterocyclic ring may optionally be substituted by one or moresubstituent listed as optional substituents for aryl. In addition,adjacent groups on the heteroaryl or heterocyclic ring may combine toform a 5- to 7-membered carbocyclic, aryl, heteroaryl or heterocyclicring, which in turn may be substituted as above. Nonlimiting examples ofheterocylics and heteroaromatics are pyrrolidinyl, tetrahydrofuryl,tetrahydrofuranyl, pyranyl, purinyl, tetrahydropyranyl, piperazinyl,piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl,pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl,aziridinyl, furyl, furanyl, pyridyl, pyridinyl, pyridazinyl,pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-thiadiazole, indazolyl, triazinayl, 1,3,5-triazinyl, thienyl,isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, quinolyl,isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl, quinazolinyl,quinoxalinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, xanthinyl, hypoxanthinyl, pyrazole, imidazole,1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine,triazolopyridinyl or pteridinyl wherein said heteroaryl or heterocyclicgroup can be optionally substituted with one or more substituentselected from the same substituents as set out above for aryl groups.Functional oxygen and nitrogen groups on the heteroaryl group can beprotected as necessary or desired. Suitable protecting groups caninclude trimethylsilyl, dimethylhexylsilyl, 1-butyidimethylsilyl, andt-butyidiphenylsilyl, trityl or substituted trityl, alkyl groups, acylgroups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl.

The term “thienyl”, alone or in combination, refers to a five membercyclic group wherein the ring contains one sulfur atom and two doublebonds.

The term “benzothienyl”, alone or in combination, refers to a fivemember cyclic group wherein the ring contains one sulfur atom and twodouble bonds fused to a phenyl ring.

The term “aryloxy”, alone or in combination, refers to an aryl groupbound to the molecule through an oxygen atom.

The term “heteroaryloxy”, alone or in combination, refers to aheteroaryl group bound to the molecule through an oxygen atom.

The term “aralkoxy”, alone or in combination, refers to an aryl groupattached to an alkyl group which is attached to the molecule through anoxygen atom.

The term “heterocyclearalkoxy” refers to a heterocyclic group attachedto an aryl group attached to an alkyl-O— group. The heterocyclic, aryland alkyl groups can be optionally substituted as described above.

The terms “halo” and “halogen”, alone or in combination, refer tochloro, bromo, iodo and fluoro.

The terms “alkoxy” or “alkylthio”, alone or in combination, refers to analkyl group as defined above bonded through an oxygen linkage (—O—) or asulfur linkage (—S—), respectively. The terms “lower alkoxy” or “loweralkylthio”, alone or in combination, refers to a lower alkyl group asdefined above bonded through an oxygen linkage (—O—) or a sulfur linkage(—S—), respectively.

The term “acyl”, alone or in combination, refers to a group of theformula C(O)R′, wherein R′ is an alkyl, aryl, alkaryl or aralkyl group,or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups areas defined above.

The term “acetyl”, alone or in combination, refers to the radical—C(O)CH₃.

The term “amino”, alone or in combination, denotes the radical —NH₂ or—NH—.

The term “nitro”, alone or in combination, denotes the radical —NO₂.

The term “substituted”, means that one or more hydrogen on thedesignated atom or substituent is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and the that the substitution results in a stablecompound. When a subsitutent is “oxo” (keto) (i.e., ═O), then 2hydrogens on the atom are replaced.

The term “alditol”, as referred to herein, and unless otherwisespecified, refers to a carbohydrate in which the aldehyde or ketonegroup has been reduced to an alcohol moiety. The alditols of the presentinvention can also be optionally substituted or deoxygenated at one ormore positions. Exemplary substituents include hydrogen, halo,haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives,alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl,ester, carboxylic acid, amide, amino acid, amino acid esters and amides,phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime,hydrazine, carbamate, phosphonic acid, and phosphonate,. Particularexemplary substituents include amine and halo, particularly fluorine.The substituent or alditol can be either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Second Edition, 1999, hereby incorporated by reference. Thealditol may have 3, 4, 5, 6 or 7 carbons. Examples of useful alditolsare those derived from reduction of monosaccharides, includingspecifically those derived from the reduction of pyranose and furanosesugars.

The term “carbohydrate”, as referred to herein, and unless otherwisespecified, refers to a compound of carbon, hydrogen and oxygen thatcontains an aldehyde or ketone group in combination with at least twohydroxyl groups. The carbohydrates of the present invention can also beoptionally substituted or deoxygenated at one or more positions.Carbohydrates thus include substituted and unsubstitutedmonosaccharides, disaccharides, oligosaccharides, and polysaccharides.The saccharide can be an aldose or ketose, and may comprise 3, 4, 5, 6,or 7 carbons. In one embodiment the carbohydrates are monosaccharides.In another embodiment the carbohydrates are pyranose and furanosesugars.

As used herein, the term “patient” refers to warm-blooded animals ormammals, and in particular humans, who are in need of the therapydescribed herein. The term “host”, as used herein, refers to aunicellular or multicellular organism, including cell lines and animals,and preferably a human.

Synthesis of the Active Compounds

The compounds of the present invention can be readily prepared by thoseskilled in the art of organic synthesis using commonly known methods,many of which are described by J, March, in Advanced Organic Chemistry,4^(th) Edition (Wiley Interscience, New York, 1992) and D. N. Dnar inThe Chemistry of Chalcones and Related Compounds (Wiley-Interscience,New York, 1981), incorporated herein by reference.

Compounds of the present invention are prepared either by reacting aheteroaryl- or heterocyclic-substituted aryl or heteroaryl ketone with asuitably substituted aryl aldehyde or by reacting a suitably substitutedaryl ketone with a heteroaryl- or heterocyclic-substituted aryl orheteroaryl aldehyde. This reaction, which is a condensation reaction, issuitably carried out under base- or acid-catalyzed conditions. Thereaction may be suitably carried out in water or protic organic solventssuch as lower alcohols (e.g. methanol, ethanol, tert-butanol), lowercarboxylic acid (e.g. formic acid, glacial acetic acid, propionic acid),or in aprotic organic solvents such as ethers (e.g. tetrahydrofuran,dioxane, diethyl ether), liquid amides (e.g. dimethylformamide,hexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons (e.g.toluene, benzene), or mixtures of such solvents. When carrying out thereaction under basic conditions, the base may be selected from sodium,lithium, potassium, barium, calcium, magnesium, aluminum, ammonium, orquarternary ammonium hydroxides, lower alkoxides (e.g. methoxides,ethoxides, tert-butoxides), carbonates, borates; oxides, hydrides, oramides of lower secondary amines (e.g. diisopropyl amides, methylphenylamides). Primary aromatic amines such as aniline, free secondary aminessuch as dimethyl amine, diethyl amine, piperidine, or pyrrolidine,tertiary amines such as pyridine, as well as basic ion exchange resinsmay also be used. Alternatively, a phase-transfer catalyst such as cetyltrimethyl ammonium chloride can also be used to facilitate the reaction,particularly when water is the solvent.

Alternatively, the aldol condensation reaction can also be carried outin an aprotic solvent such as tetrahydrofuran (THF) with an organicbase. The preferred solvent is THF and the preferred base is lithiumdiisopropylamide (LDA). In this manner an aldol reaction may take placefirst and the subsequent dehydration reaction may take place during anaqueous workup.

Acid catalysts may be selected from hydrogen chloride, hydrogen bromide,hydrogen iodide, sulfuric acid, sulfonic acids (such asparatoluenesulfonic or methansulfonic acid), lower carboxylic acid (suchas formic, acetic, or propionic acid), lower halogenated carboxylic acid(such as trifluoroacetic acid), Lewis acids (such as BF₃, POCl₃, PCl₅,FeCl₃), or acid ion exchange resins.

The reaction may be carried out at temperatures in the range of −80° C.to +150° C., preferrably in the range of ⁰° C. to +100° C., and morepreferably at room temperature. The time of reaction may be from 30minutes to approximately 24 hours.

Compounds of the invention may be isolated as either mixtures of cis (Z)and trans (E) geometric isomers or either pure trans (E) isomers. Ifdesired, either the mixtures or the pure trans isomers may be isomerizedto the corresponding predominantly cis (Z) iomers using methods wellknown in the literature.

In the above reactions, it may be preferred or necessary to protectvarious sensitive or reactive groups present in the starting materialsso as to prevent said groups from interfering with the reactions. Suchprotection may be carried out in a well-known manner as taught byTheodora W. Green and Peter G. M. Wuts, in Protective Groups in OrganicChemistry Third Edition (Wiley, 1999) or using methods from referencescited therein or of the like. The protecting group may be removed afterthe reaction in a manner known per se.

The following schemes will prove useful to those skilled: in the art inmanufacturing the compounds of the invention:

Legend for All Schemes:

1. R, R′, R″, R′″, and R″″ can be any substitution including H;

2. R, R′, R″, R′″, and R″″ can be suitabaly functionalized;

3. R, R′, R″, R′″, and R″″ can represent multiple substitutions;

4. Two adjacent R, R′, R″, R′″, or R″″ can form a ring;

5. Dashed double bond can be at any location of a ring;

6. Y, Y′, Y″, and Y′″ independently represent N(H), O, or S,

7. X and X′ independently represent Cl, Br, or I;

8. Each R, R′, R″, R′″, R″″, Y, Y′, Y″, Y′″, X or X′ is independent ineach scheme;

9. HetAr represents suitably substituted heterocyclic aryl;

10. Cy represents cyclohexyl.

EXAMPLES

The following examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Allintermediates and final products have been completely characterized byconventional proton NMR, mass spectral analyses and standard analyticalmethods known to those skilled in the art.

Example 1

1-(2,2-Bis-hydroxymethyl-benzo[1,3]dioxol-5-yl)-3E-3,4-dimethoxy-5-thiophen-2-yl-phenyl)propenone

Ex-1A: Catechol (2.2 g, 20 mmol) was dissolved in acetone. Diethyldibromomalonate (7.0 g, 22 mmol) and potassium carbonate (2.76 g) wereadded, and the mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, and water was added to theresidue. The residue was extracted with dichloromethane, and the organicphase was washed with brine, dried over magnesium sulfate andevaporated. Chromatography (hexanes/ethyl acetate, 4:1) gave 3.9 g ofbenzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester. ¹H-NMR (CDCl₃) δ6.90-6.97 (m, 4H), 4.37(q, J=7 Hz, 4H), 1.32(t, J=7 Hz, 6H).

Ex-1B: [Bis(ethoxycarbonyl)methyldenedioxy]benzene obtained from Ex-1A(3.9 g, 14.7 mmol) was dissolved in THF (100 mL) and cooled withice-water. Lithium aluminum hydride (1 M solution in THF, 44 mL) wasadded dropwise, and the mixture was stirred overnight. The reaction wascarefully quenched with saturated sodium sulfate until there was nofurther bubbling. The mixture was stirred overnight, then filtered, andthe filtrate was dried over magnesium sulfate. Chromatography(dichloromethane/methanol, 10:1) gave 0.5 g of the desired(2-hydroxymethyl-benzo[1,3]dioxol-2-yl)-methanol. ¹H-NMR (CDCl₃) δ 6.82(s, 4H), 3.94 (d, J=7 Hz, 4H), 1.98 (t, J=7 Hz, 2H).

Ex-1C: Aluminum chloride (1.3 g) was added to nitromethane followed bythe addition of acetyl chloride (1.86 g). Then(2-hydroxymethyl-benzo[1,3]dioxol-2-yl)methanol obtained from Ex-1B (0.5g) in nitromethane was added dropwise. The mixture was stirredovernight. Water was added to the reaction mixture, and it was extractedwith dichloromethane. The organic phase was washed with brine, driedover magnesium sulfate and evaporated. Chromatography gave 0.28 g of5-acetyl-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester. ¹H-NMR(CDCl₃) δ 7.56 (d, J=7 Hz, 1H), 7.43 (s, 1H), 6.85 (d, J=7 Hz, 1H), 4.42(s, 4H), 2.53 (s, 3H), 2.05 (s, 6H).

Ex-1D: A solution of 5-bromo-3,4-dimethoxybenzaldehyde (10.23 g, 41.7mmol) in 359 mL of ethylene glycol dimethyl ether was purged withnitrogen gas for 30 min. The solution was treated withtetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol),thiophene-2-boronic acid (8.01 g, 62.6 mmol), and a solution of 2 Nsodium carbonate 72 mL, 3.45 mmol). The reaction was refluxed for 16 h.The reaction mixture was concentrated, diluted with an aqueous solutionof saturated sodium bicarbonate (75 mL), and extracted withdichloromethane (2×100 mL). The organic layer was dried over sodiumsulfate and concentrated to a brown solid. The crude material waspurified by silica gel chromatography (1:1 ethyl acetate/hexanes) togive 9.42 g (90%) of the desired3,4-dimethoxy-5-(thien-2-yl)benzaldehyde product. ¹H-NMR (300 MHz,CDCl₃) δ 9.94 (s, 1H), 7.79 (d, 1H), 7.57 (dd, 1H), 7.41 (d, 1H), 7.36(d, 1H), 7.13 (dd, 1H), 3.97 (s, 3H), 3.93 (s, 3H).

5-Acetyl-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester obtainedfrom Ex-1C (0.28 g, 1.11 mmol) and3,4-dimethoxy-5-(thien-2-yl)benzaldehyde obtained from Ex-1D (0.275 g,1.11 mmol) were dissolved in ethanol, and 50% sodium hydroxide solution(0.4 mL) was added. The mixture was stirred at room temperatureovernight. Most of the solvent was removed under reduced pressure, andwater was added to the remainder. The resulting product was extractedwith dichloromethane. The organic phase was dried over magnesium sulfateand evaporated. Chromatography gave 0.19 g (38%) of the title compoundas a yellow solid, m.p. 74-80° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.74 (d,1H), 7.63 (dd, 1H), 7.49-7.55 (m, 3H), 7.38 (d, 1H), 7.37 (d, 1H), 7.12(dd, 1H), 7.07 (d, 1H), 6.88 (d, 1H), 3.99 (s, 4H), 3.98 (s, 3H), 3.88(s, 3H). Anal. Calculated for C₂₄H₂₂O₇S: C, 63.42; H, 4.88; S, 7.06;found: C, 63.46; H, 5.11; S. 6.55.

Example 2

1-(2,2-Bis-hydroxymethyl-benzo[1,3]dioxol-5-yl)-3E-(4-thiophen-2-yl-phenyl)-propenone

Ex-2A: 4-(Thien-2-yl)benzaldehyde was obtained in a similar manner asdescribed in Ex-1D from 4-bromobenzaldehyde. ¹H-NMR (CDCl₃) δ 10.00 (s,1H), 7.88 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H), 7.46 (d, J=4 Hz, 1H),7.39-7.41 (m, 1H), 7.12-7.15 (m, 1H).

The title compound was obtained when5-acetyl-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester fromEx-1C was condensed with 4-(Thien-2-yl)benzaldehyde from Ex-2A in asimilar manner as described in Ex-1. Yellow solid, mp 166-168° C., 23.6%yield. ¹H-NMR (CDCl₃) δ 7.77 (d, J=15 Hz, 1H), 7.60-7.65 (m, 5H), 7.51(d, J=2 Hz, 1H), 7.45 (d, J=15 Hz, 1H), 7.37-7.38 (m, 1H), 7.32(d, J=5Hz, 1H), 7.09 (dd, J=4, 5 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 3.96 (d, J=7Hz, 4H). MS m/z=394 ([M]⁺, 50%), 363 (100%). HRMS (EI) Calcd. forC₂₂H₁₈O₅S: 394.0875. Found: 394.0869.

Example 3

4-[3E-(5Benzo[b]thien-2-yl-2,4dimethoxyphenyl)-acryloyl]-benzoic acid

Ex-3A: A sample of 5-bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol)was dissolved in ethylene glycol dimethyl ether (50 mL).Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was added, andthe mixture was stirred at room temperature under nitrogen for 5 min.Benzo[b]thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonatesolution (2 M, 20 mL) were added. The mixture was stirred at refluxunder nitrogen for 24 hours. Upon cooling to room temperature, themixture was poured into water and extracted with ethyl acetate. Theorganic phase was dried over sodium sulfate and evaporated. Silica gelchromatography (hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) ofthe desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde. ¹H NMR(CDCl₃) δ 10.36 (s, 1H), 8.20 (s, 1H), 7.83-7.78 (m, 2H), 7.68 (s, 1H),7.36-7.27 (m, 2H), 6.54 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H).

An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20 g),benzo[b]thiophene-2-boronic acid (16 g) and THF (200 mL) weresequentially charged into a clean reaction vessel fitted with a refluxcondenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen wasbubbled into the resulting solution for 20 min followed by thesequential addition of KF (10 g), and Pd(¹Bu₃P)₂ (0.417 g). The solutionwas immediately heated to 60° C. and aged for 1.5 h. (Note: The HPLCassay at this point routinely indicated complete consumption of5-bromo-2,4-dimethoxybenzaldehyde, <0.5 area % ofbenzo[b]thiophene-2-boronic acid along with 0.5 area % of an unknown(0.55 RRT). These impurities are removed during crystallization.) Uponcompletion, as determined by HPLC, the reaction was diluted with H₂O(200 mL) and transferred to a separatory funnel containing EtOAc (200mL) and H₂O (200 mL). The layers were cut and the aqueous layer wasextracted with EtOAc (100 mL). The combined organic cuts were filteredthrough a pre-washed pad of solka floe (5 g). The pad of solka floe andspent catalyst were washed with fresh EtOAc (200 mL) and this washcombined with the batch. The resultant filtrate was batch concentratedand solvent switched to 33 wt %5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde in THF in preparationfor crystallization. (Note: The internal temperature during batchconcentration should be kept above 45° C. to prevent prematurecrystallization.) The resulting THF solution of5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde was then charged withheptane (20 mL) and slowly cooled to ambient temperature.Crystallization was then completed with the slow addition of heptane(175 mL) and cooling to 4° C. After aging for 1 h, the batch wasfiltered and then dried on the filter funnel under a stream of N₂. Thesemi-wet cake was then transferred to clean trays and dried to aconstant weight in the vacuum oven (40° C., 20 in Hg) affording 23.74 g(97% yield) of desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehydeas a light orange crystalline solid, m.p. 134-136° C. HPLC assay of thissolid indicated >99.9 LCAP. ¹H-NMR identical as above.

To a solution of 4-acetylbenzoic acid (1.50 g, 9.1 mmol) and5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (3.27 g,11.0 mmol) in N,N-dimethylformamide (76 mL) was added a solution ofsodium hydroxide (5 M, 7.3 mL, 36.5 mmol). The reaction mixture wasallowed to stir at room temperature for 2 h and was then diluted withwater to a volume of 150 mL. The solution was washed withdichloromethane and acidified with concentrated sulfuric acid to pH=3.The resulting solution was then extracted with dichloromethane. Thedichloromethane extract was washed with brine, dried over sodium sulfateand concentrated. The resulting oily product solidified in ethanol. Thesolid was further stirred in ethanol for one day and collected byfiltration. The solid was washed with ethanol, then dried in vacuo toafford the title compound as a yellow solid (2.2 g, 54%). ¹H NMR (300MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H),7.82 (d, 1H), 7.32 (m, 2H), 6.86 (s, 1H), 4.08 (s, 3H), 4.00 (s, 3H).Anal. Calculated for C₂₆H₂₀O₅S.⅙H₂O: C, 69.78; H, 4.58; S, 7.17; found:C, 69.95; H, 4.69; S, 7.15. HPLC purity: 97.9% (area percentage).

An alternative procedure:5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (42.3 g),4-acetylbenzoic acid (22.1 g), MeOH (250 mL) and DMF (600 mL) weresequentially charged into a clean reaction vessel fitted with amechanical stirrer and nitrogen inlet adapter. After completedissolution, LiOMe (10.5 g) was added in one portion and the resultingsolution was aged at 40° C. for 2 h. Upon completion, as determined byHPLC, the reaction mixture was transferred to a separatory funnelcontaining cold H₂O (800 mL, precooled to 10 deg C.). An additional 400mL cold H₂O was used to rinse the reaction vessel and this rinse wasalso added to the separatory funnel. The combined aqueous was washedwith iPrOAc (500 mL) and then acidified to a pH of 3 with 6 N HCl (ca.60 mL). The resulting heterogeneous solution was aged for 30 min andthen the precipitate was filtered, washed with 70% EtOH (100 mL) anddried on the filter funnel under a stream of N₂ affording desired acid 5as a crude yellow solid. The crude dry product and THF (260 mL) werecharged into a clean reaction vessel fitted with a mechanical stirrerand nitrogen inlet adapter. Heptane (30 mL) was slowly added to theresulting solution over 30 min and then aged resulting incrystallization. Additional heptane (270 mL) was added over 1 h, agedfor an additional 1 h and then filtered. The reaction vessel was thenrinsed with 70% EtOH (100 mL) and this rinse was added to the filtercake. The wet cake was then transferred to a clean reaction vesselcontaining 70% EtOH (750 mL) and the resulting heterogeneous mixture wasstirred overnight. The product was then filtered, rinsed with fresh 70%EtOH (100 mL) and then dried on the filter funnel under a stream of N₂.The semi-wet cake was then transferred to clean trays and dried to aconstant weight in the vacuum oven (40° C., 20 in Hg) affording 52.05 g(87% yield) of desired4-[3-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-E-acryloyl]-benzoicacid 5 as a yellow crystalline solid, m.p. 231-232° C. (dec.). HPLCassay of this solid indicated >99.9 LCAP. ¹H-NM identical as above.

Example 4

4-[3E-(4-Pyrimidin-5yl-phenyl)-acryloyl]-benzoic acid

Ex-4A: 4-Pyrimidin-5-yl-benzaldehyde was obtained pyrimidine-5-boronicacid and 4-bromobenzaldehyde in a similar manner as described in Ex-3A,88.6% yield. ¹H-NMR (CDCl₃) δ 10.11 (s, 1H), 9.28 (s, 1H), 9.01(s, 2H),8.05 (d, J=8 Hz, 2H), 7.77 (d, J=8 Hz, 2H).

The title compound was obtained in a similar manner as described in Ex-3from 4-pyrimidin-5-yl-benzaldehyde (Ex-4A) and 4acetylbenzoic acid.Yellow solid, mp>260° C., 45% yield. ¹H-NMR (DMSO-d₆) δ 9.21 (s, 2H),9.19 (s, 1H), 8.24 (d, J=9 Hz, 2H), 8.01-8.09 (m, 5H), 7.9 (d, J=6 Hz,2H), 7.81 (d, J=15 Hz, H), MS m/z=330 ([M]⁺, 100%). HRMS (EI) Calcd. forC₂₀H₁₄N₂O₃: 330.1004. Found: 330.1000.

Example 5

4-[3E-(4-Thiazol-2-yl-phenyl)acryloyl]-benzoic acid

Ex-5A: 4-Thiazol-2-yl-benzaldehyde was prepared from 4-bromobenzaldehydeand thiazole-2-boronic acid in a similar manner as described in Ex-3A,82% yield. ¹H-NMR (CDCl₃) δ 10.07 (s, 1H), 8.15 (d, J=8 Hz, 2H),7.95-7.98 (m, 3H), 7.45 (d, J=3 Hz, 1H). HMRS (EI) calcd. for C₁₀H₇NOS:189.0248; found: 189.0242.

The title compound was obtained in a similar manner as described in Ex-3from 4-thiazol-2-yl- benzaldehyde (Ex-5A) and 4-acetylbenzoic acid.Yellow solid, mp 232-235° C., 20% yield. ¹H- NMR (CDCl₃) δ 8.24 (d, J=9Hz, 2H), 8.11 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 7.93 (d, J=3 Hz,1H), 7.86 (d, J=15 Hz, 1H), 7.74(d, J=9 Hz, 2H), 7.57 (d, J=15 Hz, 1H),7.41 (d, J=3 Hz, 1H), MS m/z=335 ([M]⁺, 100%). HRMS (EI) Calcd. forC₁₉H₁₃NO₃S: 335.0616. Found: 335.0618.

Example 6

4-[3E-2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-6A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g), thiophene-2-boronicacid (11.6 g) and THF (200 mL) were sequentially charged into a cleanreaction vessel fitted with a reflux condenser, mechanical stirrer andnitrogen inlet adapter. Nitrogen was bubbled into the resulting solutionfor 20 min followed by the sequential addition of KF (10.1 g), andPd(¹Bu₃P)₂ (0.424 g). The solution was immediately heated to 60° C. andaged for 1.5 h. The reaction was diluted with H₂O (200 mL) andtransferred to a separatory funnel containing EtOAc (200 mL) and H₂O(200 mL). The layers were cut and the aqueous layer was extracted withEtOAc (100 mL). The combined organic cuts were filtered through apre-washed pad of solka floc (5 g). The pad of solka floe and spentcatalyst were washed with fresh EtOAc (200 mL) and this wash combinedwith the batch. The resultant filtrate was concentrated to dryness. Thecrude product was dissolved in THF (38 mL) and crystallized upon heptane(152 mL) addition. The product was filtered and then dried to a constantweight in the vacuum oven (38° C., 20 in Hg) affording 19.32 g (94%yield) of desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde as a lightoff- white solid, m.p. 125-126° C. ¹H-NMR (300 MHz, CDCl₃): 10.34 (s,1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.5 and 1.5 Hz), 7.31 (dd, 1H, J=5.2and 1.5 Hz), 7.07 (dd, 1H, J=5.2 and 3.5 Hz), 6.51 (s, 1H), 4.02 (s,3H), 3.99 (s, 3H).

2,4-Dimethoxy-5-thiophen-2-yl-benzaldehyde from Ex-6A (7.81 g),4-acetylbenzoic acid (4.9 g), MeOH (60 mL) and DMF (150 mL) weresequentially charged into a clean reaction vessel fitted with a stir barand nitrogen inlet adapter. After complete dissolution LiOMe (4.60 g)was added and the resulting solution was aged for 5 h. The reaction wasdiluted with H₂O (200 mL) and transferred to a separatory funnelcontaining iPrOAc (100 mL). The layers were cut and the aqueous layerwas acidified to a pH of 1 with 3 N HCl. The resulting precipitate wasfiltered and then dried on the filter funnel under a stream of N₂. Thecrude product was then dissolved in THF (60 mL) and crystallized withthe addition of heptane (60 mL). The product was filtered and then driedto a constant weight in the vacuum oven affording 8.9 g (75% yield) ofthe title compound as a yellow solid, m.p. 213-216° C. ¹H-NMR (300 MHz,CDCl₃): 8.20 (d, 2H, J=8.5 Hz), 8.09 (d, 1H, J=16.1 Hz), 8.06 (d, 2H,J=8.5 Hz), 7.85 (s, 1H), 7.52 (d, 1H, J=16.1 Hz), 7.40 (m, 1H), 7.30(dd, 1H, J=5.2 and 1.7 Hz), 7.08 (dd, 1H. J=5.2 and 3.6 Hz), 6.53 (s,1H), 3.98 (s, 3H), 3.97 (s, 3H); EIMS m/z=394 (M+). Anal. calc. forC₂₂H₁₈O₅S: C, 66.99; H, 4.60; S, 8.13; found: C, 66.71; H, 4.59; S,8.10.

Example 7

2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid

The title compound was obtained starting from5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A and2-acetylbenzoinc acid in a similar manner as described in Ex-3. Yellowsolid, mp 220-223° C. (dec.). ¹H-NMR (DMSO-d₆) δ 8.01 (s, 1H), 7.88 (d,J=7.3 Hz, 1H), 7.80-7.75 (m, 2H), 7.45-7.24 (m, 7H), 7.11 (d, J=16.2 Hz,1H), 6.79 (s, 1H), 4.00 (s, 3H), 3.88 (s, 3H). MS m/z=445 (M+, 100%).

Example 8

4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

The title compound was obtained in a similar manner as described in Ex-3from 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde (Ex-1D) and4-acetylbenzoic acid. Yellow solid, mp 231° C. ¹H-NMR (DMSO-d₆) δ 8.23(d, 2H), 8.08 (d, 2H), 7.96 (d, 1H), 7.90 (m, 1H), 7.77 (m, 2H), 7.59(d, 1H), 7.54 (m, 1H), 7.13 (dd, J=4, 4 Hz, 1H). MS m/z=395 ([M+H]⁺,100%).

Example 9

2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid, sodium salt

To a solution of 2-acetyl-benzoic acid (0.75 g, 4.6 mmol) and5-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde (Ex-3A, 1.64 g, 5.5mmol) in N,N-dimethylformamide (38 mL) was added sodium hydroxide (5M,3.7 mL, 18.5 mmol). The reaction mixture was allowed to stir for 2 hoursat ambient temperature and was diluted with water (50 mL) and sodiumcarbonate (2M, 20 mL). The aqueous solution was extracted withdichloromethane. A yellow precipitate formed in dichloromethane and wascollected by filtration, washed with dichloromethane, dried in vacuo togive the title compound as a yellow solid (1.53 g, 67%), mp 214-217° C.(dec). ¹H-NMR (DMSO-d₆) δ 7.93-7.87 (m, 3H), 7.77(d, J=8.0 Hz, 2H),7.33-7.26 (m, 4H), 7.09-7.06 (m, 2H), 7.01 (d, J=17.0 Hz, 1H), 6.78 (s,1H), 3.99 (s, 3H), 3.88 (s, 3H). MS m/z=467([M+Na]⁺, 75%), 445 ([M+H]⁺,100%). Anal. (C₂₆H₁₉O₅SNa.1.3H₂O) Calc. C, 63.55, H, 4.35, S, 6.52,found C, 63.74, H, 4.44, S, 6.55.

Example 10

4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

The title compound was obtained by condensing 4-(thien-2-yl)benzaldehydefrom Ex-2A and 4-acetylbezoic acid in a similar manner as described inEx-3. Yellow solid, 56% yield, mp>260° C. ¹H-NMR (DMSO-d₆) δ 8.01-8.08(m, 4H), 7.72 (d, J=8 Hz, 2H), 7.68 (s, 2H), 7.61 (d, J=8 Hz, 2H), 7.41(d, J=4 Hz, 1H), 7.35 (d, J=4 Hz, 1H), 7.04 (dd, J=4, 8 Hz, 1H). MSm/z=334([M+Na]⁺, 100%). Anal. (C₂₂H₁₄O₃S) Calc. C, 71.84; H, 4.22; S,9.59; found C, 71.44; H, 4.32; S, 9.43.

Example 11

1-(4-Amino-phenyl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-propenone

A suspension of 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde (1.8 g, 7.4mmol) from Ex-1D in an aqueous solution of 5 N potassium hydroxide (37mL) was treated with cetyltrimethyl ammonium chloride (39 mL, 29.6 mmol)and 4-aminoacetophenone (1.0 g, 7.4 mmol). The reaction was stirred for16 h at room temperature. The reaction mixture was titrated with 6 MH₂SO₄ to a pH of 7. The mixture was extracted with dichloromethane (2×75mL). The organic layer was washed with aqueous NaHCO₃ (2×25 mL), brine,dried over sodium sulfate, and concentrated to a yellow foam. The crudematerial was purified by silica gel chromatography (1:1 ethyl acetateand hexanes) to give 720.0 mg (27%) of the title compound as a yellowsolid, mp. 67-710C. ¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d, 2H), 7.75 (d,1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.13 (d,1H), 7.11 (m, 1H), 6.72 (d, 2H), 4.16 (s, 2H), 3.97 (s, 3H), 3.87 (s,3H). Anal. calculated for C₂₁H₁₉NO₃S.⅕H₂O: C, 68.60; H, 5.28; S, 8.72;found C, 68.51; H, 5.40; S, 8.69. MS (Pos. Ion ES): calcd forC₂₁H₂₀NO₃S: m/z=366 [M+H]⁺, found: m/z=366 [M+H]⁺.

Example 12

1-(4-Amino-phenyl)-3E-(4-thiophen-2-yl-phenyl)-propenone

The title compound was prepared from 4-(thien-2-yl)benzaldehyde (Ex-2A)and 4-aminoacetophenone in a similar manner as described in Ex-11.Yellow solid, 45% yield, mp 185-187° C. ¹H-NMR (CDCl₃) δ 7.95 (d, 2H),7.79 (d, 1H), 7.65 (m, 41), 7.55 (d, 1H), 7.39 (d, 1H), 7.33 (dd, J=5, 5Hz, 1H), 7.11 (dd, J=5, 5 Hz, 1H), 6.71 (d, 2H), 4.16 (s, 2H). MSm/z=305 ([M]⁺, 100%). Anal. calculated for C₁₉H₁₅NOS: C, 74.72; H, 4.95;S, 10.50; found C, 74.60; H, 5.05; S, 10.42.

Example 13

1-(4-Amino-phenyl)-3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-propenone

The title compound was prepared from5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A) and4-aminoacetophenone in a similar manner as described in Ex-11. Yellowsolid, 24% yield, mp 98-104° C. ¹H-NMR (CDCl₃) δ 8.10 (d, 1H), 7.95 (m,3H), 7.82 (m, 2H), 7.67 (s, 1H), 7.60 (d, 1H), 7.32 (dd, J=8.8 Hz, 2H),6.71 (d, 2H), 6.57 (s, 1H), 4.11 (br s, 2H), 4.02 (s, 3H), 3.99 (s, 3H).MS m/z=415 ([M]⁺, 39%), 384 (100%). Anal. calculated forC₂₅H₂₁NO₃S.⅓H₂O: C, 71.24; H, 5.18; S, 7.61; found C, 71.63; H, 5.18; S:7.55.

Example 14

N-{4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-methanesulfonamide

Ex-14A: A solution of1-(4-amino-phenyl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-propenone(Ex-11, 472.2 mg, 1.3 mmol) and triethylamine (398.63 μL, 2.86 mmol) wasstirred in 20 mL of anhydrous dichloromethane. The mixture was treatedwith mesyl chloride (100 μL, 1.3 mmol). The reaction mixture was stirredfor 16 hours and heated gently for another 4 hours. The crude materialwas purified by silica gel chromatography (1:3 ethyl acetate/hexane) togive 337.0 mg (quantitative) of1-[4-bis-(methanesulfonyl)aminophenyl]-3E-[(3,4-dimethoxy-5-(thien-2-yl)phenyl]-propenone.¹H-NMR (300 MHz, CDCl₃) δ 8.06 (d, 2H), 7.76 (d, 1H), 7.53 (m, 2H), 7.49(d, 2H), 7.38 (m, 1H), 7.36 (d, 1H), 7.10 (m, 1H), 7.08 (m, 1H), 3.94(s, 3H), 3.86 (s, 3H), 3.42 (s, 6H).

A solution of1-[4-bis-(methanesulfonyl)aminophenyl]-3E-[(3,4-dimethoxy-5-(thien-2-yl)phenyl]-propenone(378.86 mg, 0.73 mmol) from Ex-14A in tetrahydrofuran (6.6 mL) wastreated with aqueous 1N NaOH (1.4 mL, 1.4 mmol). The reaction wasstirred at room temperature for 1 h. The reaction was titrated with 1 NHCl to a pH of 6. The crude material was purified by silica gelchromatography (5% MeOH/CH₂Cl₂ with 1% acetic acid) to give 269.2 mg(83%) of the title compound as a solid, 83% yield, mp. 71-75° C. ¹H-NMR(300 MHz, CDCl₃) δ 8.04 (d, 2H), 7.76 (d, 1H), 7.52 (m, 2H), 7.40 (d,1H), 7.37 (m, 1H), 7.29 (d, 2H), 7.10 (m, 1H), 7.08 (m, 1H), 3.95 (s,3H), 3.86 (s, 3H), 3.12 (s, 1H), 3.09 (s, 3H). MS (Pos. Ion ES): calcdfor C₂₂H₂₂NO₅S₂: m/z=444 [M+H]⁺, found: m/z=444 [M+H]⁺. HRMS m/z: calc.444.0939, found 444.0953.

Example 15

{3-[4-13E-4-Thiophen-2-yl-phenyl)-acryloyl]-phenyl}-ureido)-acetic acidethyl ester

A solution of 1-(4-amino-phenyl)₃-(4-thiophen-2-yl-phenyl)-propenone(Ex-12, 250 mg, 0.80 mmol) and isocyanato-acetic acid ethyl ester (105.7mg, 0.80 mmol) in toluene (15 mL) was refluxed for 16 hours. Thereaction mixture was cooled to room temperature and the crude productprecipitated out of solution. The material was suctioned filtered anddried on hi-vac to give 280.2 mg (79%) of the title compound as a yellowsolid, mp 209-212° C. ¹H-NMR (DMSO-d6) δ 9.29 (br s, 1H), 8.08 (d, 2H),7.90 (m, 3H), 7.71 (d, 3H), 7.60 (m, 4H), 7.14 (t, 1H), 6.61 (t, 1H),4.09 (q, 2H), 3.86 (dd, J=2,6 Hz, 2H), 1.17 (t, 3H). MS m/z=435([M+H]^(+, 100)%). HRMS m/z: calc. 435.1378, found 435.1375.

Example 16

(3-[Ethoxycarbonylmethylaminocarbonyl]-3-{4-[3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-ureido)-aceticacid ethyl ester

A solution of1-(4-aminophenyl)-3E-[(3,4-dimethoxy-5-(thien-2-yl)phenyl]-propenone(Ex-11, 500 mg, 1.37 mmol) and ethyl isocyanatoacetate (177 mg, 1.37mmol) in anhydrous methylene chloride (20 mL) was stirred at roomtemperature for 5 hours. Due to no reaction, the reaction mixture wasconcentrated, diluted with toluene (20 mL), treated with ethylisocyanatoacetate (177 mg, 1.37 mmol), and refluxed for 14 hours. Thereaction was concentrated, diluted with methylene chloride (50 mL), andwashed with water (3×50 mL). The organic portion was collected, driedover sodium sulfate, and concentrated over silica gel. The crudematerial was purified by silica gel chromatography (50-75% ethylacetate/hexanes) to give 178.0 mg (210%) of the title compound as ayellow solid, mp 83-86° C. ¹H-NMR (CDCl₃) δ 8.09 (d, 2H), 7.76 (d, 1H),7.55 (m, 2H), 7.65 (d, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.11 (m, 2H),4.17 (q, 4H), 4.01 (d, 4H), 3.97 (s, 3H), 3.88 (s, 3H). MS m/z=646([M+Na]⁺, 100%). Anal. calculated for C₃₁H₃₃N₃O₉S: C, 59.70; H, 5.33; S,5.14; found C, 60.18; H, 5.38; S, 5.17.

Example 17

4-[3-{4-(thien-2-yl)phenyl}-3-oxo-E-propenyl]-benzoic acid, sodium salt

Ex-17A: 4′-Bromoacetophenone (3.98 g, 20 mmol) was dissolved in ethyleneglycol dimethyl ether and then the solution was degassed with nitrogenfor 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2mmol) was added, and the solution was further degassed for 10 minutes.Thiophene-2-boronic acid (3.07 g, 24 mmol) was added followed by theaddition of sodium carbonate solution (2 M, 45 mL). The mixture wasstirred at reflux under nitrogen overnight. Most of the solvent wasremoved, and water was added to the remainder. The solid was filteredout and recrystallized from ethanol and water to give 3.85 g of thedesired 4′-(thien-2-yl)acetophenone as a solid, 95% yield. ¹H-NMR(CDCl₃) δ 7.97: (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.44 (d, J=4 Hz,1H), 7.38 (d, J=5 Hz, 1H), 7.11-7.14 (m, 1H), 2.62 (s, 3H). HMRS (EI)calcd. for C₁₂H₁₀OS: 202.0452; found: 202.0454.

4′-(Thien-2-yl)acetophenone obtained from Ex-17A (0.81 g, 4 mmol) and4-carboxybenzaldehyde (0.6 g, 4 mmol) were dissolved indimethylformamide (20 mL). Sodium hydroxide solution (5 M, 3.2 mL) wasadded over 30 minutes at room temperature, and the mixture was stirredfor another 30 minutes at room temperature. The precipitate was filteredoff and recrystallized from hot water to give the title compound as ayellow solid, 29% yield, m.p.>260° C. ¹H-NMR (300 MHz, DMSO-4) δ 8.17(d, 2H), 7.89 (d, 1H), 7.87 (d, 2H), 7.81 (d, 2H), 7.76 (d, 2H), 7.72(d, 1H), 7.69 (d, 1H), 7.64 (d, 1H), 7.17 (dd, 1H). Anal. calculated forC₂₀H₁₃O₃NaS.½H₂O: C, 65.74; H, 3.86; S, 8.78; found: C, 65.66; H, 4.04;S, 9.04.

Example 18

4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid

The title compound was prepared by acidifying its sodium salt fromEx-17. Yellow solid, mp 260-265° C., 67% yield. ¹H-NMR (DMSO-d₆) δ 8.18(d, J=8 Hz, 2H), 8.00 (d, J=15 Hz, 1H), 7.91-7.94 (m, 4H), 7.82 (d, J=8Hz, 2H), 7.77-7.79 (m, 1H), 7.71(d, J=3 Hz, 1H), 7.66 (d, J=5 Hz, 1H),7.16-7.19 (m, 1H), MS m/z=334 ([M]⁺, 100%). HRMS (EI) Calcd. forC₂₀H₁₄O₃S: 334.0664. Found: 334.0669.

Example 19

4-[3-(2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoic acid

Ex-19A: 1-(2-Methoxy-4-thiophen-2-yl-phenyl)-ethanone was prepared from4-iodo-2-methoxyacetophenone in a similar manner as described in Ex-17A.¹H-NMR (CDCl₃) δ 7.53 (d, J=7 Hz, 1H), 7.37 (dd, J=2, 5 Hz, 1H), 7.06(dd, J=4, 6 Hz, 1H), 6.98-7.00 (m, 1H), 6.88-6.95 (m, 2H), 3.84 (s, 3H),2.10 (s, 3H).

The title compound was prepared by condensing1-(2-methoxy-4-thiophen-2-yl-phenyl)-ethanone (Ex-19A) and4-carboxybenzaldehyde in a similar manner as described in Ex-17 exceptan acidic workup. Yellow solid, mp 193-195° C. ¹H-NMR (CDCl₃) □ 7.70 (d,J=8 Hz, 2H), 7.38 (d, J=8 Hz, 1H), 7.07-7.16 (m, 4H), 6.75-6.80 (m, 4H),6.42 (d, J=16 Hz, 1H), 3.67 (s, 3H), MS m/z=364 ([M]⁺, 100%). Anal.Calculated for C₂₁H₁₆O₄S: C, 69.21; H, 4.43; S, 8.80; found: C, 69.02;H, 4.56; S, 8.75.

Example 20

4-[3E-(4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-20A: A solution of 3-bromo-4-flouro-benzaldehyde (5.0 g, 24.6 mmol)and thiophene-2-boronic acid (4.7 g, 37.0 mmol) in ethylene glycoldimethyl ether (100 mL) was stirred at room temperature under nitrogenfor 15 min. Then tetrakis(triphenylphosphine)-palladium(0) (2.8 g, 2.42mmol) and a sodium carbonate solution (2 M, 33 mL) were added, and theresulting mixture was refluxed under nitrogen overnight. Upon cooling toroom temperature the reaction was poured into water (100 mL) andextracted with ethyl acetate (2×100 mL). The organic phase was driedover magnesium sulfate, and the solvent was removed under reducedpressure. Silica gel chromatography (hexane/ethyl acetate, 1:1) gave 4.8g (95%) of the desired 4-fluoro-3-(thiophen-2-yl)-benzaldehyde productas a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 10.0 (s, 1H), 8.18 (dd, 1H,J=7.3 and 2.4 Hz), 7.80 (m, 1H), 7.56 (dd, 1H, J=3.7 and 1.7 Hz), 7.44(d, 1H, J=5.1 Hz), 7.36 (m, 1H), 7.16(dd, 1H, J=5.1 and 3.7 Hz).

Ex-20B: A solution of 4-fluoro-3-(thiophen-2-yl)-benzaldehyde (1.11 g,5.38 mmol) from Ex-20A and pyrrolidine (13.0 g, 183.0 mmol) indimethylformamide (30 mL) was treated with solid K₂CO₃ (1.7 g, 12.3mmol), and the resulting mixture was stirred at reflux for 1 week. Uponcooling to room temperature, the reaction was poured into water (100 mL)and extracted with ethyl acetate (2×100 mL). The organic phase was driedover magnesium sulfate, and the solvent was removed under reducedpressure. Silica gel chromatography (hexane/ethyl acetate, 2:1) gave 400mg (29%) of the desired 4-pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehydeproduct as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 9.75 (s, 1H),7.71-7.74 (m, 2H), 7.30 (dd, 1H, J=5.1 and 1.6 Hz), 7.02 (dd, 1H, J=5.1and 3.7 Hz), 6.96 (m, 1H), 6.81 (d, 1H, J=10.1 Hz), 3.15 (m, 4H), 1.84(m, 4H).

4-Pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde (400 mg, 1.55 mmol)from Ex-20B and 4-acetylbenzoic acid (255 mg, 1.55 mmol) were dissolvedin dimethylformamide (30 mL). Sodium hydroxide solution (5 N, 1.25 mL)was added in one portion, and the mixture was stirred at roomtemperature overnight. The reaction was diluted with water (100 mL) andwashed with ethyl acetate (100 mL). The aqueous phase was acidified withconc. HCl and extracted with ethyl acetate (2×100 mL). The organic phasewas dried over magnesium sulfate and concentrated under reducedpressure. Silica gel chromatography (100% ethyl acetate) followed byrecrystallization from ethanol provided 80 mg (13%) of the titlecompound as a solid, m.p. 212-214° C. with decomposition. ¹H-NMR (300MHz, CDCl₃) δ 8.21 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.80 (d,1H, J=15.3 Hz), 7.58 (d, 1H, J=1.9 Hz), 7.52 (dd, 1H, J=8.5 and 1.9 Hz),7.33 (m, 1H), 7.32 (d, 1H, 15.3 Hz), 7.01-7.06 (m, 2H), 6.82 (d, 1H, 7.9Hz), 3.12 (m, 4H), 1.84 (m, 4H). MS m/z=403 ([M]⁺, 100%). HRMS (EI)Calcd. for C₂₄H₂₁NO₃S: 403.1242. Found: 403.1251.

Example 21

4-[3E-{4-Fluoro-3-(thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid

4-Fluoro-3-thiophen-2-yl-benzaldehyde (1.0 g, 4.85 mmol, from Ex-20A)and 4-acetylbenzoic acid (0.80 g, 4.87 mmol) were dissolved indimethylformamide (55 mL). Sodium hydroxide solution (5 N, 3.88 mL) wasadded in one portion, and the mixture was stirred at room temperaturefor 3 h. The reaction was diluted with water (100 mL) and washed withethyl acetate (100 mL). The aqueous phase was acidified with conc. HCland extracted with ethyl acetate (2×100 mL). The organic phase was driedover magnesium sulfate and concentrated under reduced pressure.Recrystallization from ethanol provided 0.90 g (53%) of the titlecompound as a solid, m.p. 242-244° C. ¹H-NMR (300 MHz, d₆-DMSO) δ 13.31(bs, 1H), 8.32 (dd, 1H, J=8.2 and 2.0 Hz), 8.24 (d, 2H, J=8.2 Hz), 8.07(d, 2H, J=7.9 Hz), 7.98 (d, 1H, J=16.1 Hz), 7.92 (m, 1H), 7.80 (d, 1H,J=16.1 Hz), 7.69-7.73 (m, 2H), 7.41 (dd, 1H, 10.8 and 9.2 Hz), 7.20 (m,1H). MS m/z=352 ([M]⁺, 50%), 343 (100%). HRMS (EI) Calcd. forC₂₀H₁₃FO₃S: 352.0569. Found: 352.0571.

Example 22

1-(4-Mercapto-phenyl)-3E-(4-thiophen-2-yl-phenyl)propenone

To a solution of 4-mercaptoacetophenone (prepared according to EuropeanPatent Application 0271307) (0.57 g, 3.74 mmol) and4-(thien-2-yl)-benzaldehyde (0.70 g, 3.74 mmol, Ex. 2A) inN,N-dimethylformamide (20 mL) was added a solution of sodium hydroxide(5 M, 3 mL). The solution was allowed to stir at room temperature for 3h. The reaction mixture was then acidified with hydrochloric acid (0.5M) to pH 3. The precipitate was collected by filtration, washed withwater, and stirred in ethanol overnight. The resulting yellow solid wascollected by filtration, washed with ethanol, and dried in vacuo toafford 0.68 g (56%) of the title compound as a solid, m.p.>110° C.(dec). MS (direct probe) m/z=322 (M+). ¹H-NMR (CDCl₃) δ 7.98-8.01 (d,1H), 7.90-7.93 (d, 1H), 7.797.84 (d, 2H), 7.61-7.66 (m, 3H), 7.33-7.53(m, 4H), 7.10-7.25 (m, 2H).

Example 23

{4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-phenylthio}-aceticacid

Ex-23A: To a solution of methyl bromoacetate (1.01 mL, 10.7 mmol) inpotassium hydroxide (5M, 20 mL) was added benzenethiol (1.0 mL, 9.7mmol). The reaction mixture was allowed to stir overnight at ambienttemperature. The cloudy solution was then acidified to pH 3. Theresulting solid was filtered, washed with water and dried in vacuo toobtain phenylthioacetic acid (0.55 g). The aqueous filtrate wasextracted with dichloromethane. The solution of dichloromethane waswashed with brine, dried over sodium sulfate and concentrated to obtainadditional phenylthioacetic acid (1.49 g). ¹H NMR (CDCl₃) δ 743-7.40 (m,2H), 7.34-7.23 (m, 3H), 3.67 (s, 2H).

Ex-23B: To a mixture of alumina chloride (5.5 g, 41.0 mmol) in carbondisulfide (100 mL) was added acetyl chloride (1.17 mL, 16.5 mmol)followed by addition of phenylthioacetic acid (Ex-23A, 1.38 g, 8.2 mmol)and nitromethane (15 mL). The reaction mixture was allowed to stirovernight at ambient temperature and then was poured into ice containingsulfuric acid (6M). The insoluble solid was filtered, washed with water.After dried in vacuo, the solid was washed with toluene (2×60 mL),filtered and dried under reduced pressure to obtain(4-acetylphenylthio)acetic acid (1.28 g, 74%), m.p. 151-153° C. (Lit.156-158° C.). ¹H NMR (DMSO-d₆) δ 12.80 (bs, 1H), 7.84 (d, J=9 Hz, 2H),7.36 (d, J=9 Hz, 2H), 3.92 (s, 2H), 2.49 (s, 3H).

The title compound was prepared by condensing (4-acetylphenylthio)aceticacid (Ex-23B) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde(Ex-3A) in a similar manner as described in Ex-22. Yellow solid, mp136-138° C. (dec.). ¹H-NMR (DMSO-d₆) δ 8.35 (s, 1H), 8.08 (d, J=7.4 Hz,2H), 8.03 (d, J=16.3 Hz, 1H), 7.93-7.87 (m, 3H), 7.82 (d, J=7.0 Hz, 1H),7.42 (d, J=7.9 Hz, 2H), 7.37-7.27 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H),3.99 (s, 3H), 3.93 (s, 2H). MS m/z=491 ([M+H]⁺, 100%).

Example 24

1-(4-Methylthiophenyl)-3E-(4-thiophen-2-yl-phenyl)-propenone

To a mixture of 1-(4-mercapto-phenyl)-3E-(4-thien-2-yl-phenyl)-proenone(Ex-22, 0.33 g, 1.02 mmol) and potassium carbonate (0.54 g, 3.9 mmol) inN,N-dimethylformamide (15 mL) was added iodomethane (0.32 mL, 5.1 mmol).The reaction mixture was allowed to stir at ambient temperature for 2hours. The insoluble material was filtered. The solution was dilutedwith ethyl acetate. The solution of ethyl acetate was washed withhydrochloric acid (0.5 M), sodium carbonate (2M) and brine, dried oversodium sulfate, and concentrated. The crude product was purified byflash chromatography. Elution with ethyl acetate (33%, v/v, in hexane)gave the title compound (20 mg, 6%) as a yellow solid, mp 138-140° C.¹H-NMR (CCDl₃) δ 7.98 (d, J=7.8 Hz, 2H), 7.89-7.86 (m, 1H), 7.83 (d,J=15.3 Hz, 1H), 7.76 (s, 3H), 7.53 (d, J=15.1 Hz, 1H), 7.41 (d, J=3.7Hz, 1H), 7.35-7.31 (m, 3H), 7.13-7.10 (s, 1H), 2.54 (m, 3H). MS m/z=336(M⁺, 100%).

Example 25

Difluoro-{4-[3E-(4-thiophen-2-yl-phenyl)acryloyl]-phenylthio}-aceticacid, sodium salt

Ex-25A: To a solution of 4-mercaptoacetophenone (prepared according topublished procedure, European Patent Application 0271307) (1.16 g, 7.6mmol) and ethyl bromodifluoroacetate (1.2 mL, 9.15 mmol) inN,N-dimethylformamide (20 mL) was added potassium carbonate (3.2 g, 22.9mmol). The reaction mixture was allowed to stir overnight at ambienttemperature and then was diluted with ethyl acetate. The combinedsolution of ethyl acetate was subsequently washed with water,hydrochloric acid (0.5M), brine, dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography. Elutionwith ethyl acetate (33%, v/v, in hexane) gave(4-acetyl-phenylthio)-difluoro-acetic acid ethyl ester (1.38 g, 66%). ¹HNMR (CDCl₃) δ 7.97 (d, J=8 Hz, 2H), 7.90 (d, J=8 Hz, 2H), 4.29 (q, J=7Hz, 2H), 2.62 (s, 3H), 1.29 (t, J=7 Hz, 3H).

The title compound was prepared by condensing(4-acetyl-phenylthio)-difluoro-acetic acid ethyl ester (Ex-25A) and4-(thien-2-yl)benzaldehyde (Ex-2A) in a similar manner as described inEx-22. Yellow solid, 3% yield, mp 118-2200C. ¹H-NMR (CCDl₃) δ 8.11 (d,J=7.9 Hz, 2H), 7.95-7.90 (m, 3H), 7.75-7.70 (m, 3H), 7.66 (m, 3H), 7.59(d, J=5.0 Hz, 1H), 7.16-7.13 (m, 1H). MS m/z=415 ([M−Na]⁺, 50%), 321(100%).

Example 26

4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzenesulfonamide

Ex-26A: To a solution of 4-acetyl-benzenesulfonyl chloride (Hoffman, R.V. Org. Syn. VII, 508; 4.18 g, 19.1 mmol) in acetone (30 mL) was addedammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0° C. The reactionmixture was allowed to stir at 0° C. for 30 min. The precipitate wasfiltered and the residue was washed with water and dried in vacuo toafford 4-acetyl-benzenesulfonamide as a white solid (3.54 g, 93%). ¹HNMR (DMSO-d₆) δ 8.10 (d, J=9 Hz, 2H), 8.03 (d, J=9 Hz, 2H), 4.86 (bs,2H), 2.65 (s, 3H).

To a solution of 4-acetyl-benzsulfonamide (Ex-26A, 0.44 g, 2.2 mmol) and4-thiophen-2-yl-benaldehde (Ex-2A, 0.50 g, 2.7 mmol) in DMF (18 mL) wasadded a solution of NaOH (5 M, 1.77 mL, 8.8 mmol) dropwise. The reactionmixture was allowed to stir at ambient temperature. The reaction wasquenched after 2 hours with water. The precipitate was filtered, washedwith water, dried in vacuo and purified by stirring in aqueous ethanolovernight. The title compound was collected as a yellow solid (0.45 g,55%), mp>2450C. ¹H-NMR (DMSO-d₆) δ 8.22 (d, J=8.6 Hz, 2H), 7.96-7.89 (m,6H), 7.77-7.72 (m, 5H), 7.64 (d, J=4.0 Hz, 1H), 7.60 (d, J=4.6, 1H),7.15 (m, 1H), 6.65 (bs, 1H). MS m/z=369 ([M+H]⁺, 100%).

Example 27

3E-3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-1-H-indol-5-yl)propenone

To a solution of 1-(1H-indol-5-yl)-ethanone (Yang, Y., et al.,Heterocycles, 1992, 34(6), 1169-1175) (0.26 g, 1.63 mmol) and3,4-dimethoxy-5-(thien-2-yl)-benzaldehyde (0.45 g, 1.80 mmol, Ex-1D) inethanol (30 mL) was added a solution of sodium hydroxide (50%, 0.65 mL,16 mmol). The reaction mixture was allowed to stir overnight at roomtemperature. The solution was concentrated. The residue was treated withsulfuric acid (1 M), and the cloudy solution was extracted withdichloromethane. The combined dichloromethane extracts were washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate, andconcentrated. The residue was purified by column chromatography (silicagel, EtOAc/hexane: 1/3 then 1/1) to give 0.17 g (26%) of the titlecompound as a yellow solid, m.p. 184.5-186° C. MS (direct probe):m/z=389 (M+). ¹H-NMR (300 MHz, CDCl₃) δ 8.43 (s, 1H), 7.99 (d, 1H),7.12-7.83 (m, 10H), 6.73 (s, 1H), 3.99 (s, 3H), 3.88 (s, 3H).

Example 28

3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-1-(1-methyl-1H-indol-5-yl)-propenone

Ex-28A: To a solution of 1-(1H-indol-5-yl)-ethanone (Yang, Y. et al,Heterocycles, 1992, 34(6), 1169-1175; 0.45 g, 2.8 mmol) were addediodomethane (3 mL) and cesium carbonate (2.3 g, 7.1 mmol). The reactionmixture was allowed to stir at 55° C. for 1.5 day during whichadditional iodomethane (11 mL) was added. The reaction was quenched withwater. The aqueous solution was extracted with ether. The solution ofether was washed with saturated solution sodium bicarbonate, brine,dried over sodium sulfate and concentrated. The crude product waspurified by flash chromatography. Elution with ethyl acetate (33%, v/v,in hexane) gave 1-(1-methyl-1H-indol-5-yl)-ethanone (0.25 g, 51%). ¹HNMR (CDCl₃) δ 8.30 (s, 1H), 7.91 (dd, J=1.2, 8.1 Hz, 1H), 7.34 (d, J=8.6Hz, 1H), 7.12 (d, J=3.2 Hz, I), 6.61 (d, J=3.0, 1H), 3.82 (s, 3H), 2.66(s, 3H).

The title compound was prepared by condensing 1-(1-methyl-1H-indol-5-yl)-ethanone (Ex-28A) and3,4-dimethoxy-5-(thien-2-yl)benzaldehyde (Ex-1D) in a similar manner asdescribed in Ex-27. Yellow solid, 43% yield, mp 70-71-C. ¹H-NMR (CDCl₃)δ 8.41(s, 1H), 8.00 (dd, J=1 Hz, 7 Hz, 1H), 7.80 (d, J=15 Hz, 1H), 7.63(d, J=15.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.43-7.40 (m, 2H), 7.15-7212 (m,3H), 6.66 (d, J=3 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H).Anal. (C₂₄H₂₁NOS.0.25H₂O) Calc. C, 70.65; H, 5.31; N, 3.43; S, 7.86;found C, 70.64; H, 5.35; N, 3.43; S, 7.90.

Example 29

4-3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicAcid

Ex-29A: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolvedin dichloromethane (50 mL) and cooled to 0° C. using an ice-water bath.Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise tothe cooled solution and stirred for 2 h at 0° C. The mixture was warmedto room temperature and stirred for an additional 1 h and the resultingyellow precipitate was collected. Recrystallization (ethylacetate/hexanes) yielded 7.1 g (80%) of5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, m.p. 63-640C.¹H- NMR (300 MHz, CDCl₃) δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H),6.48 (s, 1H), 3.95 (s, 3H). Anal. Calcd. for C₈H₇BrO₃: C, 41.59; H,3.05. Found: C, 41.86; H, 3.05.

Ex-29B: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde obtained from Ex-29A(1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) weredissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into thesolution for 10 min followed by the sequential addition of potassiumfluoride (0.80 g, 14 mmol, spray-dried) andbis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). Thesolution was immediately heated to 60° C. and aged for 1.5 h. Uponcompletions as determined by HPLC, the reaction was diluted with water(25 mL) and extracted with ethyl acetate (3×30 mL). The combined organicextracts were dried over sodium sulfate and concentrated to a brownsolid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46g (97%) of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde as a yellowsolid, m.p. 118-119-C. ¹H-NMR (300 MHz, CDCl₃) δ 11.48 (s, 1H), 9.79 (s,1H), 7.72 (s, 1H), 7.37 (dd, 1H), 7.31 (dd, 1H), 7.08 (dd, 1H), 6.54 (s,1H), 3.98 (s, 3H). Anal. Calcd. for C₈H₇O₃S: C, 61.52; H, 4.30; S,13.69. Found: C, 61.12; H, 4.34; S, 13.56.

Ex-29C: To a solution of2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde from Ex-29B (0.10 g,0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate(0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C.Once at 80° C., 1-bromo-2-(2-methoxyethoxy)ethane (0.24 g, 1.3 mmol) wasadded dropwise in three equal portions with stirring at 1 h intervals.After the last addition, the reaction was stirred for an additional 1 hat 80° C. and cooled to room temperature. The mixture was diluted withwater (15 mL) and extracted with ethyl acetate (3×15 mL). The combinedorganic layers was sequentially washed with a saturated ammoniumchloride solution (1×15 mL), water (1×15 mL), and brine (1×15 mL), driedover sodium sulfate, and concentrated to a brown oil. Silica gelchromatography (ethyl acetate/hexanes, 4:1) afforded 0.13 g (87%) of4-methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde asa pale yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 10.38 (s, 1H), 8.12 (s,1H), 7.44 (dd, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.57 (s, 1H), 4.33 (t,2H), 4.00 (s, 3H), 3.94 (t, 2H), 3.74m, 2H), 3.59 (m, 2H), 3.40 (s, 3H).HRMS (EI) Calcd. for C₁₇H₂₀O₅S: 336.1031. Found: 336.1027.

4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehydeobtained from Ex-29C (0.13 g, 0.37 mmol) and 4-acetylbenzoic acid (0.061g, 0.37 mmol) were dissolved in a tetrahydrofuran-methanol solution (2mL, 7:3). After complete dissolution, lithium methoxide (0.057 g, 1.5mmol) was added and the resulting bright orange slurry was stirred inthe dark at room temperature for 4 h. Upon completion, as determined byHPLC, the mixture was diluted with water (10 mL), acidified with a 1 Nhydrochloric acid solution, and extracted with ethyl acetate (3×15 mL).The combined organic extracts were dried over sodium sulfate and todryness. The crude oil was taken up in ethyl alcohol (3 mL) a 60° C. toobtain complete dissolution and allowed to cool to room temperature. Theresulting precipitate was collected and dried in vacuo to yield 0.14 g(85%) of the title compound as a yellow solid, m.p. 145-146-C. ¹H-NMR(300 MHz, DMSO-d₆) δ 8.22 (m, 3H), 8.09 (d, 2H), 8.01 (d, 2H), 7.66 (dd,1H), 7.52 (d, 1H), 7.13 (dd, 1H), 6.88 (s, 1H), 4.36 (t, 2H), 4.00 (s,3H), 3.88 (t, 2H), 3.65 (m, 2H), 3.46 (m, 2H), 3.22 (s, 3H). Anal.Calcd. for C₂₆H₂₆NO₇S: C, 64.71; H, 5.43; S, 6.64. Found: C, 64.64; H,5.44; S, 6.61.

Example 30

4-[3E-(2-Fluoro-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-30A: 2-Fluoro-4-thiophen-2-yl-benzaldehyde was prepared in a similarmanner as described in Ex-3A from thiophene-2-boronic acid and4-bromo-2-fluorobenzaldehide (93% yield). ¹H-NMR (300 MHz, d₆-DMSO):10.13 (s, 1H), 7.81 (d, 1H, J=8.0 Hz), 7.76 (m, 1H), 7.67 (m, 2H), 7.59(dd, 1H J=8.0 and 2.1 Hz), 7.17 (dd, 1H J=5.2 and 3.7 Hz).

The title compound was prepared by condensing2-fluoro-4-thiophen-2-yl-benzaldehyde (Ex-30A) and 4-acetylbezoic acidin a similar manner as described in Ex-3. Yellow solid, 71% yield,m.p.>260° C. ¹H-NMR (300 MHz, d₆-DMSO): 8.19 (d, 2H, J=8.4 Hz), 8.12 (d,1H, J=8 Hz), 8.06 (d, 2H, J=8 Hz), 7.95 (d, 1H, J=16 Hz), 7.80 (d, 1H,J=16 Hz), 7.71 (d, 1H, J=3.5 Hz), 7.62 (m, 2H), 7.56 (d, 1H, J=8 Hz),7.15 (m, 1H). MS m/z=352 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₀H₁₃NO₃S:352.0569. Found: 352.0560.

Example 31

4-[3E-2,4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid

Ex-31A: 2,4-Dimethoxy-5-pyrimidin-5-yl-benzaldehyde was prepared from5-bromo-2,4-dimethoxybenzaldehyde and pyrimidine-5-boronic acid in asimilar manner as described in Ex-3A, 98% yield. ¹H-NMR (CDCl₃) δ 10.37(s, 1H), 9.15 (s, 1H), 8.87 (s, 2H) 7.86(s, 1H), 6.57 (s, 1H), 4.03 (s,3H), 3.96 (s, 3H).

The title compound was prepared by condensing2,4dimethoxy-5-pyrimidin-5-yl-benzaldehyde (Ex-31A) and 4-acetylbezoicacid in a similar manner as described in Ex-3. Yellow solid, mp>260° C.,26% yield. ¹H-NMR (DMSO-d₆) & 9.11 (s, 1H), 8.96 (s, 2H), 8.13-8.16 (m,3H), 8.01-8.09 (m, 3H), 7.90 (d, J=15 Hz, 1H), 6.85(s, 1H), 3.99 (s,3H), 3.91(s, 3H), MS m/z=391 ([M+H]⁺, 100%). HRMS (ES+) Calcd. forC₂₂H₁₈N₂O₅: 391.1294. Found: 391.1295.

Example 32

4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid

Ex-32A: 2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde wasprepared in a similar manner as described in Ex-29C from2-hydroxy-4-methoxy-5-thiophen-2-yl- benzaldehyde (Ex. 29B) andchloromethyl-cyclopropane, 18% yield. ¹H-NMR (CDCl₃) & 10.41 (s, 1H),8.24 (s, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 7.06 (t, 1H), 6.45 (s, 1H),3.95 (m, 5H), 1.31 (m, 1H), 0.68 (m, 2H), 0.40 (q, 2H).

The title compound was prepared by condensing2-cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-32B) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp 187-191° C. ¹H-NMR (DMSO-d₆) & 8.22 (d, 2H), 8.19 (s, 1H),7.01 (m, 4H), 7.62 (d, 1H), 7.47 (d, 1H), 7.09 (t, 1H), 6.76 (s, 1H),4.06 (d, 2H), 3.94(s, 3H), 1.34 (m, 1H), 0.62 (q, 2H), 0.38 (q, 2H). MSm/z=434 ([M]⁺, 82%), 363 (100%). 10%. Anal. for C₂₅H₂₂O₅S. HRMS m/z:calc. 435.1266, found 435.1266.

Example 33

4-{3E-[5-(3,5Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid

Ex-33A: 5-(3,5-Dimethyl-isoxazol-4-yl)2,4-dimethoxy-benzaldehyde wasprepared from 5-bromo-2,4-dimethoxybenzaldehyde and3,5-dimethyl-isoxazole-4-boronic acid in a similar manner as describedin Ex-3A, 75% yield. ¹H-NMR (CDCl₃) δ 10.34 (s, 1H), 7.63 (s, 1H), 6.52(s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 2.12(s, 6H).

The title compound was prepared by condensing5-(3,5-dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-33A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp>260° C., 7% yield. ¹H-NMR (DMSO-4) δ 8.15 (d, J=8 Hz, 2H),8.04 (d, J=16 Hz, 1H), 8.02 (d, J=8 Hz, 2H), 7.89 (s, 114), 7.81(d, J=16Hz, 1H), 6.79(s, 1H), 4.00 (s, 3H), 3.97(s, 3H), 2.23 (s, 3H) 2.05 (s,3H) MS m/z=407 ([M]⁺, 60%), 376 (100%). HMRS (EI) calcd. for C₂₃H₂₁NO₆:407.1369; found: 407.1375.

Example 34

4-[3E-(4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-34A: A solution of 2-hydroxy-4-methoxy-benzaldehyde (5.0 g, 32.86mmol) in dichloromethane (65 mL) was cooled to 0° C. and then pyridine(13.3 mL, 164.4 mmol) was added in 1 portion. Triflic anhydride (14.8mL, 87.97 mmol) was then added over 2 h while maintaining an internaltemperature below 5° C. The resulting solution was allowed to warm toroom temperature overnight and then was slowly poured into ice water(100 mL). After diluting further with 1 N HCl (100 mL) the solution wasextracted with dichloromethane (2×100 mL). The organic phase was washedwith sat NaHCO₃ (100 mL) and dried over magnesium sulfate. The solventwas then removed under reduced pressure. Silica gel chromatography(hexane/ethyl acetate, 1:1) gave 1.65 g (18%) of the desired trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester. ¹H-NMR (300 MHz,CDCl₃): 10.12 (s, 1H), 7.94 (dd, 1H, J=8.7 Hz), 7.03 (dd, 1H, J=8.7 and2.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 3.92 (s, 3H).

Ex-34B: A solution of trifluoro-methanesulfonic acid2-formyl-5-methoxy-phenyl ester (Ex-34A, 1.6 g, 5.63 mmol) in1,4-dioxane (15 mL) was stirred at room temperature under nitrogen for 5min. Thiophene-2-boronic acid (1.08 g, 8.44 mmol),tetrakis(triphenylphosphine)- palladium(0) (0.65 g, 0.56 mmol) and apotassium phosphate (2.2 g, 10.36 mmol) were then added and theresulting mixture was heated to 95° C. under nitrogen overnight. Uponcooling to room temperature the reaction was diluted with EtOAc (25 mL)and water (25 mL) and the layers were cut. The organic phase wasconcentrated under reduced pressure. Silica gel chromatography(hexane/ethyl acetate, 4:1) gave 1.1 g (90%) of the desired4-methoxy-2-thiophen-2-yl-benzaldehyde product. ¹H-NMR (300 MHz, CDCl₃):10.06 (s, 1H), 8.03 (m, 1H), 7.45 (m, 1H), 7.14 (m, 1H), 7.09 (m, 1H),7.00 (m, 2H), 3.91 (s, 3H).

The title compound was prepared by condensing4-methoxy-2-thiophen-2-yl-benzaldehyde (Ex-34A) and 4-acetylbenzoic acidin a similar manner as described in Ex-3. Yellow solid, 61% yield, m.p.209-211° C. ¹H-NMR (300 MHz, d₆-DMSO): 8.14 (m, 3H), 8.04 (d, 2H, J=9.2Hz), 7.89 (d, 1H, J=15.5 Hz), 7.76 (d, 1H, J=15.5 Hz), 7.70 (d, 1H,J=5.0 Hz), 7.18 (dd, 1H, J=5.6 and 3.6 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.05(dd, 1H, J=8.8 and 1.8 Hz), 6.98 (d, 1H, J=1.8 Hz), 3.83 (s, 3H). MSm/z=364 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₁H₁₆O₄S: 364.0769. Found:364.0761.

Example 35

2-[3E-2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

The title compound was prepared by condensing2,4-dimethoxy-5-(thiophen-2-yl) benzaldehyde (Ex-6A) and 2-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, 47% yield,mp 196-198° C. ¹H-NMR (DMSO-d₆) δ 8.00 (s, 1H), 7.84 (d, 1H), 7.61 (m,3H), 7.45 (m, 3H), 7.21 (d, 1H), 7.08 (t, 1H), 6.75 (s, 1H), 3.95 (s,3H), 3.86 (s, 3H). MS m/z=394 ([M]⁺, 100%). Anal. calculated forC₂₂H₁₈₀₅S: C, 66.99, H, 4.60, S, 8.13; found C, 67.08; H, 4.17, S: 7.97.

Example 36

2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-indole-1-carboxylicacid tert-butyl ester

Ex-36A: 2-(5-Formyl-2,4-dimethoxy-phenyl)indole-1-carboxylic acidtert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde andN-Boc-indole-2-boronic acid in a similar manner as described in Ex-3A.Yellow oil, 79% yield. ¹H-NMR (CDCl₃) δ 10.36 (s, 1H), 8.15 (d, J=8 Hz,1H), 7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27-7.35 (m, 1H), 7.19-7.27(m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42(s, 9H).

The title compound was prepared by condensing2-(5-formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butylester (Ex-36A) and 4-acetylbenzoic acid in a similar manner as describedin Ex-3. Yellow solid, 8% yield, mp 182-183° C. ¹H-NMR (CDCl₃) δ 8.21(d, J=8 Hz, 2H), 8.19 (d, J=13 Hz, 1H), 8.16 (d, J=7 Hz, 1H), 8.07 (d,J=8 Hz, 2H), 7.69 (s, 1H), 7.54 (d, J=7 Hz, 1H), 7.52 (d, J=13 Hz, 1H),7.29-7.35 (m, 1H), 7.23 (d, J=7 Hz, 1H), 6.55 (s, 1H), 6.50 (s, 1H),4.00 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H). MS m/z=528 ([M+H]⁺, 100%).Anal. calc. for C₃₁H₂₉NO₇—H₂O: C, 68.25; H, 5.73; N, 2.56; found: C,68.63; H, 5.62; N, 2.45.

Example 37

4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-37A: 2,6-Dimethoxy-4-thiophen-2-yl-benzaldehyde was prepared in asimilar manner as described in Ex-34A and Ex-34B. 75% yield, m.p.168-170° C. ¹H-NMR (300 MHz, CDCl₃): 10.48 (s, 1H), 7.43 (dd, 1H, J=3.6and 1.3 Hz), 7.41 (d, 1H, J=5.3 Hz), 7.13 (dd, 1H, J=5.3 and 3.6 Hz),6.79 (s, 2H), 3.96 (s, 6H).

The title compound was prepared by condensing2,6-dimethoxy-4-thiophen-2-yl-benzaldehyde (Ex-37A) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, 79% yield,m.p. 256-258° C. ¹H-NM, (300 MHz, d₆-DMSO): 8.11 (d, 1H, J=15.9 Hz),8.10 (m, 4H), 8.05 (d, 1H, J=15.9 Hz), 7.73 (d, 1H, J=3.6 Hz), 7.61 (d,1H, J=5.3 Hz), 7.16 (dd, 1H, J=5.3 and 3.6 Hz), 6.95 (s, 2H), 3.98 (s,6H). MS m/z=394 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₂H₁₈O₅S: 394.0875.Found: 394.0877.

Example 38

4-{3E-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid

Ex-38A: 5-2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-benzaldehyde wasprepared from 5-bromo-2,4-dimethoxybenzaldehyde and2,4-Dimethoxy-pyrimidin-5-boronic acid in a similar manner as describedin Ex-3A, 75% yield. ¹H-NMR (CDCl₃) δ 10.34 (s, 1H), 8.13 (s, 1H),7.74(s, 1H), 6.51 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.95(s, 3H), 3.88(s, 3H).

The title compound was prepared by condensing5-(2,4-dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-benzaldehyde (Ex-38A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp 203-205° C., 22% yield. ¹H-NMR (DMSO-d₆) δ 8.11-9.15 (m, 3H),7.99-8.06 (m, 3H), 7.88 (s, 1H), 7.76 (d, J=17 Hz, 1H), 6.76(s, 1H),3.96(s, 3H), 3.90(s, 3H), 3.83 (s, 3H) 3.81 (s, 3H). MS m/z=451([M+H]⁺). HRMS (ES+) Calcd. for C₂₄H₂₂N₂O₇: 451.1505. Found: 451.1524.

Example 39

4-[3E-(2,4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-39A: 2,4-Dimethoxy-6-thiophen-2-yl-benzaldehyde was prepared in asimilar manner as described in Ex-34A, 40% yield. ¹H-NMR (CDCl₃) δ 10.02(s, 1H), 7.40 (d, 1H), 7.07 (m, 2H), 6.58 (d, 1H), 6.50 (d, 1H), 3.93(s, 3H), 3.89 (s, 3H).

The title compound was prepared by condensing2,4-dimethoxy-6-thiophen-2-yl-benzaldehyde (Ex-39A) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, 61% yield,mp 231° C. (dec.). ¹H-NMR (DMSO-d₆) δ 8.02 (d, 2H), 7.93 (d, 2H), 7.73(m, 3H), 7.15 (t, 1H), 7.07 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H). MSm/z=394 ([M]⁺, 6%), 245 (100%). HRMS m/z: calc. 395.0953, found395.0949.

Example 40

4-{3E-[2,4-Dimethoxy-S-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoicacid

Ex-40A: 2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-benzaldehyde wasprepared from 5-bromo-2,4-dimethoxybenzaldehyde and5-methyl-thiophene-2-boronic acid in a similar manner as described inEx-3A, 100% yield. ¹H-NMR (CDCl₃) δ 10.33 (s, 1H), 8.05 (s, 1H), 7.22(d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.49 (s, 1H), 4.00 (s, 3H), 3.97(s, 3H), 2.50 (s, 3H). HMRS (EI) calcd. for C₁₄H₁₄O₃S: 262.0664; found:262.0665.

The title compound was prepared by condensing2,4-dimethoxy-5-(5-methyl-thiophen-2-yl)-benzaldehyde (Ex-40A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp 213-215° C., 27% yield. ¹H-NMR (DMSO-d₆) δ 8.18 (d, J=7 Hz,2H), 8.17 (s, 1H), 8.00-8.06 (m, 3H), 7.85 (d, J=15 Hz, 1H), 7.42(d, J=4Hz, 1H), 6.78(m, 2H), 3.96 (s, 3H), 3.95(s, 3H), 2.42 (s, 3H). MSm/z=408 ([M]⁺, 100%). HMRS (EI) calcd. for C₂₃H₂₀O₅S: 408.1031; found:408.1023.

Example 41

4-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-41A: 4-Methoxy-3-(thiophen-2-yl)-benzaldehyde was prepared from3-bromo-4-methoxybenzaldehyde and thiophene-2-boronic acid in a similarmanner as described in Ex-3A. Orange oil, 96% yield. ¹H-NMR (CDCl₃) δ9.94 (s, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.80 (dd, J=2.4, 8.4 Hz, 1H), 7.57(dd, J=1.8, 3.6 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.12 (dd, J=3.6, 5.1Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 4.02 (s, 3H). HRMS m/z: calc. 218.0402,found 218.0406.

The title compound was prepared by condensing4-methoxy-3-(thiophen-2-yl)-benzaldehyde (Ex-41A) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, mp 219-220°C., 71% yield. ¹H-NMR (DMSO-D₆) δ 13.36 (br s, 1H), 8.25-8.31 (m, 3H),8.11 (d, J=8 Hz, 2H), 7.85-7.98 (m, 3H), 7.78-7.80 (m, 1H), 7.61 (d, J=5Hz, 1H), 7.25 (d, J=9 Hz, 1H), 7.17 (dd, J=4, 6 Hz, 1H), 3.99 (s, 3H).HRMS m/z=calc. 365.0848, found 365.0833.

Example 42

4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-42A: 3-(Thiophen-2-yl)-benzaldehyde was prepared from3-bromobenzaldehyde and thiophene-2-boronic acid in a similar manner asdescribed in Ex-3A. Orange oil, 93% yield. ¹H-NMR (CDCl₃) δ 10.06 (s,1H), 8.10 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.55(dd, J=7.2, 8.4 Hz, 1H), 7.40 (dd, J=1.5, 3.6 Hz, 1H), 7.34 (dd, J=1.5,5.3 Hz, 1H), 7.11 (dd, J=3.6, 5.3 Hz, 1H). HRMS m/z: calc. 188.0296,found 188.0293.

The title compound was prepared by condensing3-(thiophen-2-yl)-benzaldehyde (Ex-42A) and 4-acetylbenzoic acid in asimilar manner as described in Ex-3. Yellow solid, mp 238° C. (dec), 71%yield. ¹H-NMR (DMSO-D₆) δ 13.40 (bs, 1H), 8.29 (d, J=8 Hz, 2H), 8.22 (s,1H), 8.13 (d, J=8 Hz, 2H), 8.04 (s, 1H), 7.87 (s, 1H), 7.83 (d, J=8 Hz,1H), 7.73 (d, J=9 Hz, 1H), 7.69 (d, J=4 Hz, 1H), 7.63 (d, J=5 Hz, 1H),7.52 (t, J=8 Hz, 1H), 7,20 (dd, J=4, 5 Hz, 1H). HRMS m/z=calc. 335.0742,found 335.0749.

Example 43

3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

The title compound was prepared by condensing2,4-dimethoxy-5-(thiophen-2-yl) benzaldehyde (Ex-6A) and 3-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, 65% yield,mp 179-182° C. ¹H-NMR (DMSO-d₆) δ 8.54 (s, 1H), 8.39 (d, 1H), 8.25 (s,1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.67 (m, 2H), 7.48 (d,1H), 7.09(t, 1H), 6.81 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H). MS m/z=394([M]⁺, 72%), 363-(100%). Anal. calculated for C₂₂H₁₈₀₅S: C, 66.99, H,4.60, S, 8.13; found C, 66.80; H, 4.60, S: 8.07.

Example 44

4-[3E-(3-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid

Ex-44A: 3-Benzo[b]thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde wasprepared through Suzuki coupling as described in Ex-3A using3-bromo-2-hydroxy-4-methoxybenzaldehyde (obtained as a minor productfrom Ex-29A). ¹H-NMR (CDCl₃) δ 12.08 (s, 1H), 9.80 (s, 1H), 7.80-7.87(m, 2H), 7.70 (s, 1H), 7.56 (d, J=9 Hz, 1H), 7.31-7.35 (m, 2H), 6.71 (d,J=9 Hz, 1H), 3.97 (s, 3H). HRMS m/z: calc. 284.0507, found 284.0502.

Ex-44B: 3-Benzo[b]thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde(Ex-44A, 57.4 mg, 0.202 mmol) was dissolved in acetone (5 mL) andpotassium carbonate (31 mg, 0.22 mmol) was added. Methyl iodide (25 uL,0.40 mmol) was added and the solution was heated to reflux for 3.5 h.After cooling, the crude reaction mix was concentrated on the rotavap.The resulting residue was taken up in 10 mL of a 1:9 mix of saturated,aqueous NH₄Cl to water and extracted with EtOAc (2×15 mL). The organicphase was dried over sodium sulfate, filtered, and concentrated toprovide 58.5 mg of 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde asan orange, oily residue which was used without further purification, 97%yield. ¹H-NMR (CDCl₃) δ 10.31 (s, 1H), 7.92 (d, J=9 Hz, 1H), 7.81-7.88(m, 2H), 7.56 (d, 1H), 7.33-7.39 (m, 2H), 6.88 (d, J=9 Hz, 1H), 3.91 (s,3H), 3.64 (s, 3H).

The title compound was prepared by condensing3-benzo[b]thiophen-2-yl-2,4-dimethoxy- benzaldehyde (Ex-44B) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp 237° C. (dec.), 64% yield. ¹H-NMR (DMSO-d₆) δ 13.37 (bs, 1H),8.20-8.25 (m, 3H), 8.11 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 1H), 7.96 (d,J=9.;Hz, 2H), 7.88-7.91 (m, 1H), 7.65 (s, 1H), 7.35-7.43 (m, 2H), 7.14(d, J=9 Hz, 1H), 3.90 (s, 3H), 3.53 (s, 3H). HRMS m/z=calc. 445.1110,found 445.1112.

Example 45

4-[3E-2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-45A: 2-Methoxy-5-(thiophen-2-yl)benzaldehyde was prepared from5-bromo-2-methoxybenzaldehyde and thiophene-2-boronic acid in a similarmanner as described in Ex-3A. ¹H NMR (CDCl₃) δ 10.49 (s, 1H), 8.07 (d,J=3 Hz, 1H), 7.79 (dd, J=3, 9.0 Hz, 1H), 7.28-7.26 (m, 2H), 7.09-7.06(m, 1H), 7.02 (d, J=9 Hz, 1H), 3.97 (s, 3H).

The title compound was prepared by condensing2-methoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-45A) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, mp 195-196°C. ¹H-NMR (DMSO-d₆) δ 8.23-8.20 (m, 3H), 8.08-7.96 (m, 4H), 7.67 (dd,J=2.1, 6.8 Hz, 1H), 7.55 (d, J=3.8 Hz, 1H), 7.49 (d, J=5.1 Hz, 1H),7.16-7.11 (m, 2H), 3.90 (s, 3H). MS m/z=364 (M⁺, 100%).

Example 46

4-[3E-(2,4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-46A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.92 g, 20.1 mmol) wasdissolved in benzene (41 mL). Ethylene glycol (3 mL, 54 mmol) andp-toluenesulfonic acid (25 mg, 0.13 mmol) were added and the solutionwas refluxed with a Dean-Stark trap attached. After 6 h, the reactionwas cooled and washed with water (1×20 mL), saturated, aqueous NaHCO₃(1×20 mL), and water (1×20 mL). The organic phase was dried over sodiumsulfate, filtered, concentrated, and dried to provide 5.32 g of2-5-bromo-2,4dimethoxy-phenyl)-[1,3]dioxolane as a faint yellow oilwhich solidified upon standing (92% yield). ¹H-NMR (CDCl₃) δ 7.67 (s,1H), 6.47 (s, 1H), 6.06 (s, 1H), 4.114.13 (m, 2H), 3.984.03 (m, 2H),3.91 (s, 3H), 3.87 (s, 3H). HRMS (ES+) Calcd. for C₁₁H₁₃BrO₄: 289.0075.Found: 289.0077.

Ex-46B: 2-(5-Bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane (Ex-46A, 4.78 g,10.5 mmol) was dissolved in dioxane (75 mL) and the solution was purgedwith nitrogen for 15 min. Pd(OAc)₂ (188 mg, 0.84 mmol), Et₃N (6.91 mL,49.6 mmol), and 2-dicyclohexylphosphino)biphenyl (1.16 g, 3.31 mmol)were added. 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (3.6 mL, 24.8 mmol)was added slowly, accompanied by gas evolution and the darkening of thereaction solution. The solution was heated at reflux for 2.5 h and thencooled. Saturated, aqueous NH₄Cl (60 mL) and water (20 mL) were addedand the solution extracted with EtOAc (1×100 mL). The organic phase wasdried over sodium sulfate, filtered, and concentrated to a dark oil. Theoil was purified via silica gel chromatography (1:1 EtOAc/hexanes aftera column pre-wash of 5% Et₃N in 1:1 EtOAc/hexanes) to provide 3.27 g of2-5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolaneas a yellow solid (with some starting borolane present), 59% yield.¹H-NMR (CDCl₃) δ 7.85 (s, 1H), 6.39 (s, 1H), 6.07 (s, 1H), 4.134.18 (m,2H), 3.98-4.02 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 1.33 (s, 9H).

Ex-46C:2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(Ex-46B, 2.22 g, 6.60 mmol, containing borolane impurity) was dissolvedin DME (60 mL) and 2-iodopyrazine (0.59 mL, 6.0 mmol) was added. 2Maqueous Na₂CO₃ (17.8 mL, 35.6 mmol) was added and the mixture was purgedwith nitrogen for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.69g, 0.60 mmol) was added and the mixture was heated at reflux for 2.5 h.After cooling, water (50 mL) was added and the mixture was extractedwith CH₂Cl₂(2×30 mL). The organic phase was washed with brine (1×20 mL),dried over sodium sulfate, filtered, and concentrated. Purification ofthe resulting yellow-orange solids via silica chromatography (50-80%EtOAc/hexanes) provided 1.02 g of2-5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine as a yellow solid(59% yield). ¹H-NMR (CDCl₃) δ9.10 (d, J=2 Hz, 1H), 8.61 (m, 1H), 8.39(d, J=3 Hz, 1H), 8.07 (s, 1H), 6.57 (s, 1H), 6.14 (s, 1H), 4.134.18 (m,2H), 4.01-4.05 (m, 2), 3.95 (s, 3H), 3.93 (s, 3H).

Ex-46D: 2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine (1.02 g,3.54 mmol) was dissolved in acetone and p-toluenesulfonic acid (100 mg,0.53 mmol) and water (5 mL) were added. The solution was stirred for 3 hat room temperature, then concentrated on the rotavap. The resultingmixture was diluted with water (50 mL) and extracted with EtOAc (3×100mL). The organic phase was washed with 25% saturated aqueous NaHCO₃,dried over sodium sulfate, filtered, and concentrated. Drying gave 0.30g of 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde as a yellow solid (18%yield). ¹H-NMR (CDCl₃) δ 10.35 (s, 1H), 9.06 (d, J=2 Hz, 1H), 8.63-8.65(m, 1H), 8.45 (d, J=2 Hz, 1H), 8.39 (s, 1H), 6.56 (s, 1H), 4.03 (s, 3H),4.01 (s, 3H). HRMS m/z: calc. 244.0848, found 244.0853.

The title compound was prepared by condensing2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde (Ex-46D) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, mp 238° C.(dec.), 4% yield. ¹H-NMR (DMSO-D₆) δ 9.04 (d, J=2 Hz, 1H), 8.75-8.76 (m,1H), 8.56 (d, J=2 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=9 Hz, 2H), 8.05-8.11(m, 3H), 7.83 (d, J=16 Hz, 1H), 6.90 (s, 1H), 4.05 (s, 3H), 4.00 (s,.3H). HRMS m/z=calc. 391.1294, found 391.1313.

Example 47

4-{3E-[4-(1-Carboxy-1-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid

Ex-47A: 5-Bromo-4-hydroxy-2-methoxy-benzaldehyde was prepared in ananalogous fashion as described in Ex-29A using4-hydroxy-2-methoxybenzaldehyde. The crude solid was slurried in waterto remove residual HBr and dried in vacuo to give the bromide as anoff-white solid (98%), mp 199-201° C. ¹H-NMR (300 MHz, DMSO-d₆) δ 11.58(s, 1H), 10.07 (s, 1H), 7.75 (s, 1H), 6.69 (s, 1H), 3.87 (s, 3H). MS(EI) m/z=230 ([M]⁺, 100%). Anal. Calcd. for C₈H₇BrO₃.¼H₂O: C, 40.79; H,3.21. Found: C, 40.66; H, 3.01.

Ex-47B: 4-Hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde was prepared inan analogous fashion as described in Ex-29B. Silica gel chromatography(ethyl acetate/hexanes, 2:1) gave the expected product as a solid (85%),mp 200° C. (dec.). ¹H-NMR (300 MHz, CDCl₃) δ 10.31 (s, 1H), 7.89 (s,1H), 7.42 (dd, 1H, J=4.8, 1.2 Hz), 7.14-7.19 (m, 2H), 6.59 (s, 1H), 6.14(brs, 1H), 3.94 (s, 3H). MS (EI) m/z: 234 ([M]⁺, 100%). Anal. Calcd. forC₁₂H₁₀O₃S.H₂O: C, 57.13; H, 4.79; S, 12.71. Found: C, 57.16; H, 4.47; S,12.48.

Ex-47C:2-(4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acidethyl ester was prepared in an analogous fashion as described in Ex-29Cusing ethyl 2-bromoisobutyrate. Silica gel chromatography (ethylacetate/hexanes, 1:1) gave the expected product as a solid (82%), mp111-113° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.14 (s, 1H), 7.45(dd, 1H, J=3.7, 1.3 Hz), 7.30 (dd, 1H, J=5.2, 1.3 Hz), 7.07 (dd, 1H,J=5.2, 3.7 Hz), 6.35 (s, 1H), 4.25 (q, 2H, J=7.2 Hz), 3.85 (s, 3H), 1.76(s, 6H), 1.23 (t, 3H, J=7.2 Hz). MS (EI) m/z=348 ([M]⁺, 100%). Anal.Calcd. for C₁₈H₂₀O₅S: C, 62.05; H, 5.79; S, 9.20. Found: C, 61.81; H,5.81; S, 9.12.

Ex-47D: To a solution of2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acidethyl ester (0.29 g, 0.83mmol) in a mixture of tetrahydrofuran, waterand methanol (9 mL, 4:1:1) was added lithium hydroxide (0.10 g, 2.49mmol) and the resulting yellow slurry was stirred at rt for 5 h. Themixture was diluted with water (5 mL) and extracted with ethyl acetate(1×5 mL). The aqueous layer was acidified with a 1 N HCl solution andextracted with ethyl acetate (3×15 mL). The combined organic layers wasdried over sodium sulfate and concentrated to afford 0.13 g (87%) of2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acidas a pale green solid, mp 183-184° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.32(s, 1H), 8.12 (s, 1H), 7.40 (d, 1H, J=3.6 Hz), 7.32 (d, 1H, J=4.8 Hz),7.08 (dd, 1H, J=4.8, 3.6 Hz), 6.47 (s, 1H), 3.86 (s, 3H), 1.78 (s, 6H).MS (EI) m/z=320 ([M]⁺, 100%). Anal. Calcd. for C₁₆H₁₆O₅S: C, 59.99; H,5.03; S, 10.01. Found: C, 60.04; H, 5.26; S, 9.70.

2-(4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid(Ex-47D, 0.23 g, 0.72 mmol) and 4-acetylbenzoic acid (0.12 g, 0.72 mmol)were dissolved in a dimethylformamide-methanol solution (5 mL, 7:3).After complete dissolution, lithium methoxide (0.11 g, 2.9 mmol) wasadded and the resulting orange slurry was stirred in the dark at roomtemperature for 4 h. Upon completion, as determined by HPLC, the mixturewas diluted with water (15 mL), acidified with a 1 N hydrochloric acidsolution, and extracted with ethyl acetate (4×25 mL). The combinedorganic extracts were dried over sodium sulfate and evaporated todryness. The crude oil was taken up in a tetrahydrofuran-heptanesolution (5 mL, 10:1) and warmed to 60° C. to obtain completedissolution and allowed to cool to room temperature. The resultingprecipitate was collected on filter paper and dried in vacuo to yield0.30 g (90%) of the title compound as a dark yellow solid, mp 135-137°C. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.23 (d, 2H, J=8.4 Hz),8.10 (d, 2H, J=8.4 Hz), 7.99 (d, 2H, J=15.6 Hz), 7.71 (d, 1H, J=3.0 Hz),7.54 (d, 1H, J=5.1 Hz), 7.14 (dd, 1H, J=5.1, 3.0 Hz), 6.49 (s, 1H), 3.85(s, 3H), 1.69 (s, 6H). MS (ESI) m/z=467 ([M+H]⁺, 100%). Anal. Calcd. forC₂₅H₂₈O₈S.EtOH: C, 63.27; H, 5.51; S, 6.26. Found: C, 63.40; H, 5.19; S,6.38.

Example 48

2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

The title compound was prepared by condensing4-methoxy-3-(thiophen-2-yl)-benzaldehyde (Ex-41A) and 2-acetylbenzoicacid in a similar manner as described in Ex-3. Beige solid with greentint, mp 79-81° C., 44% yield. ¹H-NMR (DMSO-D₆) δ 8.07 (d, J=2 Hz, 1H),7.91 (d, J=8 Hz, 1H), 7.73 (dd, J=2, 4 Hz, 1H), 7.67-7.70 (m, 2H), 7.63(dd, J=2, 7 Hz, 1H), 7.57 (dd, J=2, 5 Hz, 1H),7.50 (d, J=8 Hz, 1H), 7.22(d, J=2 Hz, 2H), 7.19 (d, J=8 Hz, 1H), 7.12 (dd, J=4, 5 Hz, 1H), 3.96(s, 3H). HRMS m/z=calc. 365.0848, found 365.0853.

Example 49

4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicacid

Ex-49A: To a solution of4-hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-47B, 0.50 g, 2.14mmol) and tri(ethylene glycol) monomethyl ether (0.38 g, 3.2 mmol) intetrahydrofuran (20 mL) was added triphenylphosphine (0.84 g, 3.2 mmol)and the resulting mixture was cooled to 0° C. Diethyl azodicarboxylate(0.55 g, 3.2 mmol) was then added drop wise, stirred at 0° C. for 30min, and allowed to warm to rt. The solution was stirred for anadditional 24 and concentrated under reduced pressure to a brown oil.Silica gel chromatography (ethyl acetate/hexanes, 8:1) afforded 0.31 g(45%) of the expected2-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-benzaldehydeas a viscous clear oil. ¹H-NMR (300 MHz, CDCl₃) δ 10.34 (s, 1H), 8.13(s, 1H), 7.48 (d, 1H, J=3.6 Hz), 7.30 (t, 1H, J=5.1 Hz), 7.06 (dd, 1H,J=5.1, 3.6 Hz), 6.56 (s, 1H), 4.34 (t, 2H, J=5.1 Hz), 3.94 (t, 2H, J=5.1Hz), 3.96 (s, 3H), 3.72-3.75 (m, 2H), 3.56-3.59 (m, 2H), 3.39 (s, 3H).MS (ESI) m/z=337 ([M+H]⁺, 100%). HRMS (EI) Calcd. for C₁₇H₂₀O₅S:336.1031. Found: 336.1028.

The title compound was prepared by condensing2-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-benzaldehyde(Ex-49A) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Yellow solid, mp 174-175° C., 61% yield. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.28 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.05-8.11 (m, 3H), 7.91 (d, 1H,J=15.3 Hz), 7.72 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=4.2 Hz), 7.11-7.15(m, 1H), 6.86 (s, 1H), 4.39 (t, 2H, J=3.9 Hz), 3.99 (s, 3H), 3.89 (t,2H, J=3.9 Hz), 3.64 (t, 2H, J=3.9 Hz), 3.48 (t, 2H, J=3.9 Hz), 3.25 (s,3H). MS (ESI) m/z=483 ([M+H]⁺, 100%). Anal. Calcd. for C₂₆H₂₆O₇S: C,64.71; H, 5.43; S, 6.64. Found: C, 64.43; H, 5.34; S, 6.54.

Example 50

4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid

Ex-50A: To a solution of3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propan-1-ol (25.0 g, 74.3 mmol) and triethylamine(22.6 g, 223 mmol) in dichloromethane (150 mL) at 0° C. was added mesylchloride (12.8 g, 111 mmol) and the resulting slurry was stirred at 0°C. for 15 min and allowed to warm to rt. The solution was stirred for anadditional 3 h at rt and diluted with water (130 mL) and ethyl acetate(350 mL). The layers were separated and the aqueous was extracted withethyl acetate (1×150 mL). The combined organic extracts were washed witha saturated sodium bicarbonate (1×200 mL), a 50% sodium chloridesolution (2×200 mL), dried over sodium sulfate and concentrated toafford 29.5 g (97%) of the expected methanesulfonic acid3-tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propylester as a yellow oil, 97% yield. ¹H-NMR (300 MHz, CDCl₃), 4.29 (d, 2H,J=5.7 Hz), 3.61-3.68 (m, 4H), 2.99 (s, 3H), 2.04-2.11 (m, 1H), 0.88 (s,18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for C₁₇H₄₀O₅SSi₂: 413.2213.Found: 413.2226.

Ex-50B:4-[3-(tert-Butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in ananalogous fashion as described in EX-29C using methanesulfonic acid3-(tert-butyl-dimethyl-silanyloxy)-2-tert-butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-50A). Silica gelchromatography (ethyl acetate/hexanes, 1:6) gave the expected product asa pale green solid, 90% yield. ¹H-NMR (300 MHz, CDCl₃) δ 10.34 (s, 1H),8.13 (s, 1H), 7.41 (dd, 1H, J=3.6, 1.2 Hz), 7.28 (dd, 1H, J=5.1, 1.2Hz), 7.05 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.22 (d, 2H, J=5.7 Hz),3.96 (s, 3H), 3.80 (d, 4H, J=5.7 Hz), 2.33 (pentet, 1H, J=5.7 Hz), 0.88(s, 18H), 0.012 (s, 12H). MS (ESI) m/z=551 ([M+H]⁺, 100%). HRMS (EI)Calcd. for C₂₈H₄₆O₅SSi₂: 550.2604. Found: 550.2593.

Ex-50C: To a solution of4-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-50B, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was addedtetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol)and the mixture was stirred at rt for 30 min. The reaction was dilutedwith ethyl acetate (50 mL) and washed with a 50% ammonium chloridesolution (1×30 mL), water (2×30 mL), brine (1×30 mL), dried over sodiumsulfate and concentrated to a crude yellow solid. Silica gelchromatography afforded 0.37 g (99%) of the expected4-3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehydeas a pale yellow solid, 90% yield, mp 144-145° C. ¹H-NMR (300 MHz,CDCl₃) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H, J=3.6, 1.5 Hz),7.30(dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.59 (s, 1H),4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 2.33(pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8 Hz). MS (ESI) m/z=323([M+H]⁺, 100%). Anal. Calcd. for C₁₆H₁₈O₅S: C, 59.61; H, 5.63; S, 9.95.Found: C, 59.34; H, 5.75; S, 9.82.

The title compound was prepared by condensing4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-50C) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Yellow solid, mp 199-201° C., 60% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.31s, 1H, 8.23 (d, 2H, J=8.7 Hz), 8.06-8.11 (m, 3H), 7.93 (d, 1H,J=15.0 Hz); 7.71 (d, 1H, J=3.3 Hz), 7.54 (d, 1H, J=5.1 Hz), 7.13-7.16(m, 1H), 6.87 (s, 1H), 4.62 (brs, 2H), 4.27 (d, 2H, J=5.1 Hz), 4.00 (s,3H), 3.62 (brs, 4H), 2.11-2.15 (m, 1H). MS (ESI) m/z=469 ([M+H]⁺, 100%).Anal. Calcd. for C₂₅H₂₄O₇S”/4H₂O: C, 63.48; H, 5.22; S, 6.78. Found: C,63.45; H, 5.29; S, 6.61.

Example 51

5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylicacid methyl ester

Ex-51A: 5-(5-Formyl-2,4-dimethoxy-phenyl)thiophene-2-carboxylic acidmethyl ester was prepared starting from 5-bromo-thiophene-2-carboxylicacid methyl ester in a similar manner as described in Ex-46A through46D. Yellow solid, 18% yield. ¹H-NMR (CDCl₃) δ 10.32 (s, 1H), 8.16 (s,1H), 7.74 (d, J=4.4 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 6.51 (s, 1H), 4.05(s, 3H), 3.98 (s, 3H), 3.90 (s, 3H). HRMS (ES+) Calcd. for C₁₅H₁₄O₅S:307.0640. Found: 307.0630.

4-Acetylbenzoic acid (24 mg, 0.15 mmol) and5-(5-formyl-2,4-dimethoxy-phenyl)-thiophene-2-carboxylic acid methylester (Ex-51A, 46 mg, 0.15 mmol) were dissolved in DMF (4 mL). Lithiummethoxide, 1M in methanol (0.29 mL) was added and the solution stirredat room temperature overnight. The reaction solution was poured intocold 1N HCl (3 mL) and extracted with EtOAc (3×20 mL); the organic phasewas washed with brine 1×10 mL), dried over sodium sulfate, filtered, andconcentrated. The resulting orange residue was purified via silica gelchromatography (0-10% MeOH/CH₂Cl₂) to provide 89 mg of yellow solidwhich still contained DMF. The solid was slurried in EtOH for severalhours, filtered, and dried to provide 31 mg of final product as a yellowsolid (47% yield). ¹H-NMR (DMSO-d₆) δ 8.47 (s, 1H), 8.23 (d, J=9 Hz,2H), 8.01-8.11 (m, 4H), 7.89 (d, J=4 Hz, 1H), 7.82 (d, J=4 Hz, 1H), 6.90(s, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 3.84 (s, 3H). HRMS (ES+) Calcd. forC₂₄H₂₀O₇S: 453.1008. Found: 453.1020.

Example 52

5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylicacid

The title compound was prepared through routine hydrolysis of5-{5-[3-(4-Carboxy-phenyl)-3-oxo-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylicacid methyl ester (Ex-51). Orange solid, mp>260° C., 43% yield. ¹H-NMR(DMSO-d₆) δ 8.43 (s, 1H), 8.26 (d, J=8 Hz, 2H), 8.01-8.12 (m, 4H), 7.82(d, J=4 Hz, 1H), 7.71 (d, J=4 Hz, 1H), 6.89 (s, 1H), 4.08 (s, 3H), 4.03(s, 3H).

Example 53

4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-53A: Reaction of 4-hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-47B) and (2-ethoxymethyl-5-hydroxymethyl-[1,3]dioxolan-4-yl)methanolwas preformed under the Mitsunobu condition using triphenylphosphine anddiethyl azodicarboxylate in THF. However, the expected product,4-(2-ethoxymethyl-5-hydroxymethyl-[1,3]dioxolan-4-ylmethoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde,was not obtained. Instead,4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde was formed via cleavageof the cyclic ethyl orthoformate group under the reaction conditions.Silica gel chromatography (ethyl acetate/hexanes, 1:2) gave 0.16 g (90%)of 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde, mp 101-1030C. ¹H-NMR(300 MHz, CDCl₃) δ 10.33 (s, 1H), 8.15 (s, 1H), 7.48 (d, 1H, J=3.6 Hz),7.29 (d, 1H, J=5.2 Hz), 7.07 (dd, 1H, J=5.2, 3.6 Hz), 6.50 (s, 1H), 4.25(q, 2H, J=7.2 Hz), 3.97 (s, 3H), 1.59 (t, 3H, J=7.2 Hz). MS (EI) m/z=262([M]⁺, 100%). HMRS (EI) Calcd. for C₁₄H₁₄O₃S: 262.0664. Found: 262.0667.

The title compound was prepared by condensing4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-53A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp 210-212° C., 76% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.31 (s,1H), 8.23 (d, 2H, J=9.0 Hz), 8.06-8.11 (m, 3H), 7.92 (d, 1H, J=16.2 Hz),7.71 (d, 1H, J=3.9 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1,3.9Hz), 6.82 (s, 1H), 4.33 (q, 2H, J=6.1 Hz), 3.99 (s, 3H), 1.48 (t, 3H,J=6.1 Hz). MS (ESI) m/z=409 ([M+H]⁺, 100%). Anal. Calcd. forC₂₃H₂₀O₅S.½H₂O: C, 66.17; H, 5.07; S, 7.68. Found: C, 65.88; H, 5.24; S,7.36.

Example 54

4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid

4-Hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-47B, 0.30 g; 0.86mmol) and 4-acetylbenzoic acid (0.13 g, 0.86 mmol) were dissolved in adimethylformamide-methanol solution (6 mL, 7:3). After completedissolution, lithium methoxide (0.12 g, 3.3 mmol) was added and theresulting red slurry was stirred in the dark at room temperature for 18h. The mixture was diluted with water (15 mL), acidified with a 1 Nhydrochloric acid solution, and extracted with ethyl acetate (4×25 mL).The combined organic extracts were dried over sodium sulfate andevaporated to dryness. The crude oil was subjected to silica gelchromatography (CH₂Cl₂:MeOH, 20:1) to yield an orange solid containingresidual amounts of starting acid. The solid was taken up in ethylalcohol (5 mL) to remove acid impurity and the resulting precipitate wascollected on filter paper and dried in vacuo to yield 0.010 g (5%) ofthe title compound as an orange solid, mp 243° C. (dec). ¹H-NMR (300MHz, DMSO-d₆) δ 8.18-8.23 (m, 3H), 8.06-8.09 (m, 2H), 8.02 (s, 1H), 7.85(d, 1H, J=15.6 Hz), 7.68 (d, 1H, J=3.6 Hz), 7.47 (d, 1H, J=5.1 Hz), 7.11(dd, 1H, J=5.1,3.6 Hz), 6.67 (s, 1H), 4.13 (s, 1H), 3.89 (s, 3H). MS(ESI) m/z=381 ([M+H]⁺, 100%). HRMS (ESI) Calcd. for C₂₁H₁₆O₅S: 381.0796.Found: 381.0800.

Example 55

4-[3E-2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-55A: 2,4-Dimethoxy-5-thiazol-2-yl-benzaldehyde was prepared from2-bromothiazole in a similar manner as described in Ex-46A through 46D.Off-white solid, 83% yield. ¹H-NMR (CDCl₃) δ 10.34 (s, 1H), 8.86 (s,1H), 7.89 (d, J=3.6 Hz, 1H), 7.36 (d, J=3.6 Hz, 1H), 6.56 (s, 1H), 4.12(s, 3H), 4.02 (s, 3H). HRMS m/z: calc. 249.0460, found 249.0461.

The title compound was prepared by condensing2,4-dimethoxy-5-thiazol-2-yl-benzaldehyde (Ex-55A) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Yellow solid, mp>260° C.,65% yield. ¹H-NMR (DMSO-d₆) δ 13.33 (bs, 1H), 8.74 (s, 1H), 8.22 (d, J=8Hz, 2H), 8.04-8.12 (m, 3H), 7.95 (d, J=2 Hz, 1H), 7.82 (d, J=16 Hz, 1H),7.76 (d, J=3 Hz, 1H), 6.94 (s, 1H), 4.14 (s, 3H), 4.05 (s, 1H). HRMSm/z=calc. 396.0906, found 396.0903.

Example 56

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)acryloyl]-benzoicacid, sodium salt

To a solution of4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid (5.77 g, 13.0 mmol) in tetrahydrofuran (50 mL) was added sodiummethoxide (0.70 g, 12.3 mmol). The reaction mixture was allowed to stirfor 2 hours at ambient temperature. The precipitate was then filtered,washed with tetrahydrofuran and dried in vacuo to give the titlecompound (5.13 g, 85%) as a yellow solid, mp>235° C. ¹H-NMR (DMSO-d₆) δ8.35 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 8.00-7.89 (m, 4H), 7.82 (d, J=7.6Hz, 1H), 7.35-7.29 (m, 4H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H). MSm/z=443 (M⁺, 100%).

Example 57

2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1-carboxylicacid tert-butyl ester

Ex-57A: 2-5-Formyl-2,4-dimethoxy-phenyl)-pyrrole-1-carboxylic acidtert-butyl ester was prepared from pyrrole-1-carboxylic acid tert-butylester-2-boronic acid in a similar manner as described in Ex-3A, 81%yield. ¹H-NMR (CDCl₃) δ 10.32 (s, 1H), 7.76 (s, 1H), 7.31-7.33 (m, 1H),6.43 (s, 1H), 6.22-6.24 (m, 1H), 6.14-6.16 (m, 1H), 3.98(s, 3H), 3.85(s, 3H), 1.40 (s, 9H). HRMS (EI) Calcd. for C₁₈H₂₁NO₅: 331.1420. Found:331.1421.

The title compound was prepared by condensing2-(5-formyl-2,4-dimethoxy-phenyl)-pyrrole-1-carboxylic acid tert-butylester (Ex-57A) and 4-acetylbenzoic acid in a similar manner as describedin Ex-3. Yellow solid, mp 205-207° C., 6% yield. ¹H-NMR (DMSO-d₆) δ 8.19(d, J=5 Hz, 2H), 8.00-8.10 (m, 3H), 7.87 (s, 1H), 7.80 (d, J=16 Hz, 1H),7.27-7.28(m, 1H), 6.71(s, 1H), 6.22-6.23 (m, 1H), 6.14-6.16 (m, 1H),3.96 (s, 3H), 3.79(s, 3H), 1.29 (s, 9H). MS m/z=476 ([M−H]⁺). HMRS (EI)calcd. for C₂₇H₂₇NO₇: 477.1788; found: 477.1793.

Example 58

4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)acryloyl]-benzoic acid

2-Hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-29B, 0.10 g, 0.43mmol) and 4-acetylbenzoic acid (0.070 g, 0.43 mmol) were dissolved in adimethylformamide-methanol solution (2.8 mL, 7:3). After completedissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and theresulting red slurry was stirred in the dark at room temperature for 18h. The mixture was diluted with water (10 mL), acidified with a 1 Nhydrochloric acid solution, and extracted with ethyl acetate (3×20 mL).The combined organic extracts were dried over sodium sulfate andevaporated to dryness. The crude oil was taken up in ethyl alcohol (5mL) and warmed to 60° C. to obtain complete dissolution and allowed tocool to room temperature. Note: the compound appears to decompose withheating. The resulting precipitate was collected on filter paper anddried in vacuo to yield 0.025 g (15%) of the title compound as a darkyellow solid, mp 125° C. (dec). ¹H-NMR (300 MHz, DMSO-d₆) δ 10.73 (s,1H), 8.18-8.22 (m, 3H), 8.09 (d, 2H, J=8.1 Hz), 8.05 (s, 1H), 7.87 (d,1H, J=14.7 Hz), 7.60 (d, 1H, J=3.0 Hz), 7.49 (d, 1H, J=4.2 Hz), 7.11(dd, 1H, J=4.2, 3.0 Hz), 6.67 (s, 1H), 3.90 (s, 3H). MS (ESI) m/z=381([M+H]⁺, 100%). Anal. Calcd. for C₂₁H₁₆O₅S.EtOH: C, 64.77; H, 5.20; S,7.52. Found: C, 64.68; H, 5.00; S, 7.77.

Example 59

4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid

Ex-59A:2-(2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acidethyl ester was prepared in an analogous fashion as described in Ex-29Cusing ethyl 2-bromoisobutyrate. Silica gel chromatography (ethylacetate/hexanes, 1:2) gave the expected product as a dark yellow solid(97%), mp 87-88° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.37 (s, 1H), 8.14 (s,1H), 7.45 (dd, 1H, J=3.6, 1.2 Hz), 7.30 (d, 1H, J=5.4 Hz), 7.07 (dd, 1H,J=5.1, 3.6 Hz), 6.42 (s, 1H), 4.25 (q, 2H, J=6.9 Hz), 3.90 (s, 3H), 1.72(s, 6H), 1.26 (t, 3H, J=6.9 Hz). MS (ESI) m/z=349 ([M+H]⁺, 100%). Anal.Calcd. for C₁₈H₂₀O₅S: C, 62.05; H, 5.79; S, 9.20. Found: C, 62.15; H,5.82; S, 9.06.

Ex-59B: 2-2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionicacid was prepared in an analogous fashion as described in Ex-47D. Thecrude solid was dried in vacuo to afford the product as a pale yellowsolid (98%), mp 187-188° C. ¹H-NMR (300 MHz, CDCl₃) δ 9.33 (s, 1H), 7.99(s, 1H), 7.47 (dd, 1H, J=3.6, 1.5 Hz), 7.37 (d, 1H, J=4.8 Hz), 7.11 (dd,1H, J=4.8, 3.6 Hz), 6.67 (s, 1H), 4.00 (s, 3H), 1.75 (s, 6H). MS (ESI)m/z=321 ([M+H]⁺, 100%). Anal. Calcd. for C₁₆H₁₆O₅S: C, 59.99; H, 5.03;S, 10.01. Found: C, 59.80; H, 5.12; S, 9.87.

2-(2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid(Ex-59B, 0.12 g, 0.39 mmol) and 4-acetylbenzoic acid (0.064 g, 0.39mmol) were dissolved in a dimethylformamide-methanol solution (2.7 mL,7:3). After complete dissolution, lithium methoxide (0.060 g, 1.6 mmol)was added and the resulting bright orange slurry was stirred in the darkat room temperature for 2 h. Upon completion, as determined by HPLC, themixture was diluted with water (15 mL), acidified with a 1 Nhydrochloric acid solution, and extracted with ethyl acetate (3×15 mL).The combined organic extracts were dried over sodium sulfate andevaporated to dryness. The crude oil was taken up in ethyl alcohol (5mL) and warmed to 60° C. to obtain complete dissolution and allowed tocool to room temperature. The resulting precipitate was collected onfilter paper and dried in vacuo to yield 0.15 g (85%) of the titlecompound as a dark yellow solid, mp 223-2250C. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.31 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.10 (d, 2K, J=8.1 Hz), 8.06 (s,1H), 7.95 (d, 1H, J=16.2 Hz), 7.69 (d, 1H, J=3.0 Hz), 7.55 (d, 1H, J=5.1Hz), 7.14 (dd, 1H, J=5.1, 3.0 Hz), 6.58 (s, 1H), 3.88 (s, 3H), 1.66 (s,6H). MS (ESI) m/z=467 ([M+H]⁺, 100%). Anal. Calcd. for C₂₅H₂₂O₇S.⅓H₂O:C, 63.55; H, 4.84; S, 6.79. Found: C, 63.39; H, 5.02; S, 6.53.

Example 60

4-{3E-[4-Methoxy-2-(2-morpholin4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid,hydrochloride

Ex-60A:4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzaldehyde wasprepared in an analogous fashion as described in Ex-29C using4-(2-chloroethyl)morpholine. Silica gel chromatography (80 to 100% ethylacetate/hexanes then 5% methanol/methylene chloride) gave of theexpected product as a off-white solid (81%). ¹H-NMR (300 MHz, CDCl₃) δ10.36 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H,J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.53 (s, 1H), 4.27 (t, 2H,J=6.3 Hz), 4.00 (s, 3H), 3.72-3.76 (m, 4H), 2.89 (t, 2H, J=6.3 Hz),2.60-2.63 (m, 4H). MS (ESI) m/z=348 ([M+H]⁺, 100%). HRMS (EI) Calcd. forC₁₈H₂₁NO₄S: 347.1191. Found: 347.1188.

4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzaldehyde(Ex-60A, 0.15 g, 0.43 mmol) and 4-acetylbenzoic acid (0.071 g, 0.43mmol) were dissolved in a dimethylformamide- methanol solution (3.0 mL,7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol)was added and the resulting bright orange slurry was stirred in the darkat room temperature for 2 h. Upon completion, as determined by HPLC, themixture was diluted with water (10 mL), acidified with a 1 Nhydrochloric acid solution, and extracted with an ethylacetate:tetrahydrofuran mixture (1:1, 6×20 mL). The combined organicextracts were dried over sodium sulfate and evaporated to dryness. Thecrude solid was slurried in ethyl alcohol (5 mL) to remove residualimpurities and the resulting solid was collected on filter paper anddried in vacuo to yield 0.21 g (98%) of the title compound as a darkyellow solid, mp: 255° C. (dec). ¹H-NMR (300 MHz, DMSO-d₆) δ 8.34 (s,1H), 8.26 (d, 2H, J=8.7 Hz), 8.11 (d, 2H, J=8.7 Hz), 8.08 (s, 1H), 7.95(d, 1H, J=15.9 Hz), 7.71 (d, 1H, J=3.3 Hz), 7.55 (d, 1H, J=4.5 Hz), 7.15(dd, 1H, J=4.5, 3.3 Hz), 6.94 (s, 1H), 4.68 (brs, 2H), 4.04 (s, 3H),3.98 (brs, 2H), 3.81-3.88 (brm, 2H), 3.70 (brs, 2H), 3.54-3.58 (brm,2H), 3.29 (brs, 2H). MS (ESI) m/z=494 ([M+H]⁺, 100%). Anal. Calcd. forC₂₇H₂₈ClNO₆S: C, 61.18; H, 5.32; Cl, 6.69; N, 2.64; S, 6.05. Found: C,61.18; H, 5.41; Cl, 6.16; N, 2.73; S, 5.87.

Example 61

2 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid

Ex-61A: 2-(5-Formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acidtert-butyl ester (Ex-36A, 2.0 g, 5.2 mmol) was dissolved in 100 ml ofTHF, and Bu₄NF (6.86 g, 26 mmol) was added. The reaction mixture wasstirred at room temperature overnight. No reaction occured at thiscondition. Then, Bu₄NF (6.86 g, 26 mmol) was added to the mixture, andthe mixture was stirred at reflux for 4 days. The reaction was about 50%completion (HPLC). The reaction mixture was poured into CH₂Cl₂, andwashed with water and brine. The organic phase was dried over MgSO₄, andconcentrated. The residue was purified by column chromatography (EtOAc:Hex, 2:1) to give 0.45 g (30%) of5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde. ¹H-NMR (CDCl₃) δ 10.37 (s,1H), 9.25 (br, 1H), 8.28 (s, 1H), 7.63(d, J=8 Hz, 1H), 7.39 (d, J=8 Hz,1H), 7.08-7.20 (m, 2H), 6.92(d, J=2 Hz, 1H), 6.56 (s, 1H) 4.11(s, 3H),4.00 (s, 3H). HMRS (EI) calcd. for C₁₇H₁₅NO₃: 281.1052; found: 281.1049.

The title compound was prepared by condensing5-(1H-indol-2-yl)-2,4dimethoxy-benzaldehyde (Ex-61A) and 4-acetylbenzoicacid in a similar manner as described in Ex-3. Red solid, mp 210-212°C., 66% yield. ¹H-NMR (Aceton-d₆) δ 10.53 (br, s, 1H), 8.32 (s, 1H),8.14-8.21 (m, 5H), 7.89 (d, J=15 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.38 (d,J=7 Hz, 1H), 6.97-7.07(m, 3H), 6.87(s, 1H), 4.07 (s, 3H), 4.02(s, 3H),MS m/z=427 ([M]⁺). HMRS (EI) calcd. for C₂₆H₂₁NO₅: 427.1420; found:427.1435.

Example 62

4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid

Ex-62A:2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehydewas prepared in a similar manner as described in Ex-29C using4-chloromethyl-3,5-dimethyl-isoxazole. ¹H-NMR (CDCl₃) δ 10.26 (s, 1H),8.14 (s, 1H), 7.45 (d, J=6 Hz, 1H), 7.32 (d, J=5 Hz, 1H), 7.07-710 (m,1H), 6.58 (s, 1H), 4.96 (s, 2H), 4.04 (s, 3H), 2.46 (s, 3H), 2.32 (s,3H).

The title compound was prepared by condensing2-(3,5-dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-62A) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Yellow solid, mp 213-215° C. ¹H-NMR (CDCl₃) δ 8.20 (d, J=9 Hz,2H), 7.88-8.03 (m, 4H), 7.58 (d, J=16 Hz, 114), 7.44 (d, J=4 Hz, 1H),7.34(d, J=5 Hz, 1H), 7.12(dd, J=4, 5 Hz, 1H), 6.63 (s, 1H), 4.97(s, 2H),4.01 (s, 31), 2.46(s, 3H), 2.34 (s, 3H). MS m/z=490 ([M+H]⁺). HRMS (ES+)Calcd. for C₂₇H₂₂NO₆S: 490.1324. Found: 490.1321.

Example 63

4-[3E-2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-43A: A solution of 2-fluoro-5-thiophen-2-yl-benzaldehyde (1.42 g,6.89 mmol) in pyrrolidine was refluxed (10 mL). After 4.5 days thereaction mixture was cooled and diluted with ethyl acetate. The solutionof ethyl acetate was washed with hydrochloric acid (0.5M) sodiumcarbonate (2M) and saturated solution of sodium bicarbonate, dried oversodium sulfate, and concentrated. The crude product was purified byflash chromatography. Elution with ethyl acetate (20%, v/v, in hexane)afforded 2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (0.5 g, 32%). ¹HNMR (CDCl₃) δ 10.14 (s, 1H), 7.94 (d, J=2 Hz, 1H), 7.62 (dd, J=2.7,9-Hz, 1H), 7.22-7.20 (m, 2H), 7.07-7.04 (m, 1H), 6.86 (d, J=9 Hz, 1H),3.41 (m, 4H), 2.01 (m, 4H).

The title compound was prepared by condensing2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (Ex-63A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Redsolid, mp 208-209-C. ¹H-NMR (DMSO-d,) δ 12.50 (bs, 1H), 8.22 (d, J=8.5Hz, 2H), 8.09-7.99 (m, 4H), 7.73 (d, J=15.5 Hz, 1H), 7.52-7.41 (m, 3H),7.10-7.07 (m, 1H), 6.93 (d, J=9.0 Hz, 1H), 3.28 (m, 4H), 1.87 (m, 4H).

Example 64

4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid

Ex-64A: To a solution of2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (10.0 g, 42.7 mmol) inN,N-dimethylformamide (100 mL) was added potassium carbonate (11.8 g,85.4 mmol) and the resulting yellow slurry was heated to 80° C. Once at80° C., methanesulfonic acid3-tert-butyl-dimethyl-silanyloxy)₂-tert-butyl-dimethyl-silanyloxymethyl)-propylester (Ex-50A, 19.5 g, 46.9 mmol) was added dropwise and the reactionwas stirred for an additional 24 h at 80° C. and cooled to roomtemperature. The mixture was diluted with water (500 mL) and extractedwith ethyl acetate (3×150 mL). The combined organic layers wassequentially washed with a saturated sodium bicarbonate solution (1×150mL), water (1×150 mL), and brine (1×150 ml), dried over sodium sulfate,and concentrated to a brown oil. Silica gel chromatography (100% ethylacetate to 10% ethyl acetate/hexanes) gave 19.0 g (81%) of2-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]4-methoxy-5-thiophen-2-yl-benzaldehydeas an off-white solid, mp 91-92° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.37 (s,1H), 8.12 (s, 114), 7.44 (dd, 1H, J=3.6, 1.2 Hz), 7.29 (d, 1H, J=5.1Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.19 (d, 2H, J=6.0 Hz),3.99 (s, 3H), 3.72-3.82 (m, 4H), 2.28 (pentet, 1H, J=6.0 Hz), 0.88 (s,18H), 0.048 (s, 12H). MS (EI) m/z=550 ([M]⁺, 100%). Anal. Calcd. forC₂₈H₄₆O₅SSi₂: C, 61.05; H, 8.42; S, 5.82. Found: C, 61.20; H, 8.74; S,5.69.

Ex-64B:2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehydewas prepared in an analogous fashion as described in Ex-50C. Silica gelchromatography (ethyl acetate/hexanes, 1:9) gave the expected product asan off-white solid. ¹H-NMR (300 MHz, CDCl₃)δ 10.17 (s, 1H), 8.03 (s,1H), 7.43 (dd, 1H, J=3.6, 1.2 Hz), 7.31 (d, 1H, J=5.1 Hz), 7.08 (dd, 1H,J=5.1, 3.6 Hz), 6.58 (s, 1H), 4.32 (d, 2H, J=6.0 Hz), 4.01 (s, 3H),3.95-3.99 (m, 4H), 2.51 (t, 2H, J=5.1 Hz), 2.33 (pentet, 1H, J=5.4 Hz).MS (EI) m/z=322 ([M]⁺, 100%). HRMS (EI) Calcd. for C₁₆H₁₈O₅S: 322.0875.Found: 322.0873.

The title compound was prepared by condensing2-(3-hydroxy-2-hydroxymethyl-propoxy)₄-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-64B) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Light orange solid, mp 219-220° C., 61% yield. ¹H-NMR (300 MHz,DMSO-d₆) δ 8.36 (s, 1H), 8.20 (d, 2H, J=7.5 Hz), 8.05-8.11 (m, 3H), 7.93(d, 1H, J=16.2 Hz), 7.67(d, 1H, J=3.0 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13(dd, 1H, J=5.1, 3.0 Hz), 6.88 (s, 1H), 4.66 (brs, 2H), 4.23 (d, 2H,J=6.3 Hz), 4.01 (s, 3H), 3.55-3.66 (m, 4H), 2.09-2.14 (m, 1H). MS (ESI)m/z=469 ([M+H]⁺, 100%). Anal. Calcd. for C₂₅H₂₄O₇S.H₂O: C, 61.72; H,5.39; S, 6.59. Found: C, 61.93; H, 5.30; S, 7.06.

Example 65

4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2yl-phenyl]-acryloyl}-benzoicacid, hydrochloride

Ex-65A: 2-3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde wasprepared in a similar manner as described in Ex-60A, 80% yield. ¹H-NMR(DMSO-D6) δ 10.36 (s, 1H), 7.90 (dd, J=3, 5 Hz, 1H), 7.82 (d, 1H), 7.48(d, 1H), 7.44 (d, 1H), 7.25 (d, 1H), 7.09 (t, 1H), 4.18 (t, 2H), 3.53(m, 4H), 3.28 (br s, 2H), 2.43 (m, 4H), 1.89 (q, 2H).

The title compound was prepared by condensing2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-65A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, 67% yield, mp 234-236° C. ¹H-NMR (DMSO-d6) δ 13.32 (br s, 1H),11.10 (br s, 1H), 8.21 (m, 3H), 8.02 (m, 3H), 7.67 (dd, J=2, 2 Hz, 1H),7.56 (d, 1H), 7.50 (d, 1H), 7.14 (m, 2H), 4.21(t, 2H), 3.86 (m, 4H),3.23 (m, 6H), 2.29 (q, 2H). MS m/z=478 ([M+H]⁺, 100%). Anal. calculatedfor C₂₇H₂₈ClNO₅S. 3/2H₂O: C, 59.94; H, 5.78; S, 5.93; found C, 60.20; H,5.65; S, 5.94

Example 66

4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride

Ex-66A:4-Methoxy-2-3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde wasprepared in a similar manner as described in Ex-60A, 78% yield. ¹H-NMR(DMSO-D6) δ 10.21 (s, 1H), 7.88 (s, 1H), 7.46 (m, 2H), 7.06 (t, 1H),6.82 (s, 1H), 4.24 (t, 2H), 4.00 (s, 3H), 3.53 (m, 4H), 3.28 (m, 2H),2.34 (m, 4H), 1.93 (q, 2H).

The title compound was prepared by condensing4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde(Ex-66A) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Yellow solid, 72% yield, mp 188-191° C. (dec). ¹UH-NMR (DMSO-d₆) δ12.63 (br s, 1H), 11.08 (br s, 1H), 8.33 (s, 1H), 8.22 (d, 2H), 8.05 (m,3H), 7.89 (d, 1H), 7.65 (d, 1H), 7.49 (d, 1H), 7.10 (t, 1H), 6.84 (s,1H), 4.30 (t, 2H), 3.98 (s, 3H), 3.84 (m, 4H), 3.21 (m, 6H), 2.28 (q,2H). MS m/z=508 ([M+H]⁺, 100%). Anal. calculated for C₂₈H₃₂ClNO₇S.H₂O:C, 59.83; H, 5.74; S, 5.70; found C, 59.69; H, 5.80; S, 5.55.

Example 67

4-[3E-(2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid

Ex-67A:2-2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl-acetamide wasprepared in an analogous fashion as described in Ex-29C using2-chloro-N,N-dimethylacetamide. Methylene chloride was used in place ofethyl acetate for the work up procedure. The crude solid was slurried inethyl acetate (25 mL) to remove residual impurities. The resulting solidwas collected on filter paper and dried in vacuo to give the expectedproduct as a pale yellow solid (85%), mp 197-198° C. ¹H-NMR (300 MHz,CDCl₃) δ 10.38 (s, 1H), 8.13 (s, 1H), 7.44 (d, 1H, J=3.6 Hz), 7.30 (dd,1H, J=5.1, 1.8 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.73 (s, 1H), 4.89 (s,2H), 3.99 (s, 3H), 3.15 (s, 3H), 2.99 (s, 3H). MS (EI) m/z=319 ([M]⁺,100%). Anal. Calcd. for C₁₆H₁₇NO₄S.⅕H₂O: C, 59.50; H, 5.43; N, 4.34; S,9.93. Found: C, 59.65; H, 5.42; N, 4.40; S, 9.69.

The title compound was prepared by condensing2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl-acetamide(Ex-47A) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Yellow solid, mp 228-229° C., 75% yield. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.31 (d, 2H, J=9.3 Hz), 8.22 (d, 2H, J=13.3 Hz), 8.08 (d, 2H, J=9.3Hz), 7.95 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13(dd, 1H, J=5.1,2.7 Hz), 6.85 (s, 1H), 5.11 (s, 2H), 3.99 (s, 3H), 3.06(s, 3H), 2.93 (s, 3H). MS (EI) m/z=465 ([M]⁺, 100%). HRMS (EI) Calcd.for C₂₅H₂₃NO₆S: 465.1246. Found: 465.1246.

Example 68

4-[3E-(4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid

Ex-68A: Methanesulfonic acid 2-[2-2-methoxy-ethoxy)-ethoxy]-ethyl esterwas prepared in an analogous fashion as described in Ex-50A usingdi(ethylene glycol) methyl ether. The crude orange oil was dried invacuo to give the expected product (oil) and was used without anyfurther purification (99%). ¹H-NMR (300 MHz, CDCl₃) δ 4.374.40 (m, 2H),3.76-3.78 (m, 2H), 3.61-3.70 (m, 6H), 3.53-3.57 (d, 2H), 3.38 (s, 3H),3.08 (s, 3H). MS (ESI) m/z=243 ([M+H]⁺, 100%). HRMS (ESI) Calcd. forC₈H₁₈O₆S: 243.0902. Found: 243.0914.

Ex-68B:4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-benzaldehyde was prepared in an analogous fashion as as described inEx-29C using methanesulfonic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester (Ex-68A). Silica gel chromatography (ethyl acetate/hexanes, 8:1)gave the expected product as a pale yellow oil (70%). ¹H-NMR (300 MHz,CDCl₃) δ 10.38 (s, 1H); 8.12 (s, 1H), 7.44 (d, 1H, J=3.6 Hz), 7.30 (d,1H, J=5.4 Hz), 7.07 (dd, 1H, J=5.4, 3.6 Hz), 6.57 (s, 1H), 4.31 (t, 2H,J=4.8 Hz), 3.99 (s, 3H), 3.94 (t, 2H, J=4.8 Hz), 3.74-3.78 (m, 2H),3.62-3.69 (m, 4H), 3.53-3.56 (m, 2H), 3.37 (s, 3H). MS (EI) m/z=380([M]⁺, 100%): HRMS (ESI) Calcd. for C₈H₁₈O₆S: 243.0902. Found: 243.0914.

The title compound was prepared by condensing4-methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-benzaldehyde(Ex-48B) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Yellow solid, mp 137-138° C., 82% yield. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.20-8.23 (m, 3H), 8.09 (d, 2H, J=8.3 Hz), 8.01 (m, 2H), 7.66 (d, 1H,J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1,3.6 Hz), 6.88 (s,1H), 4.37 (t, 2H, J=3.6 Hz), 4.01 (s, 3H), 3.89 (t, 2H, J=3.6 Hz),3.64-3.67 (m, 2H), 3.53-3.56 (m, 2H), 3.47-3.50 (m, 2H), 3.363.95 (m,2H), 3.19 (s, 3H). MS (ESI) m/z=527 ([M+H]⁺, 100%). Anal. Calcd. forC₂₈H₃₀O₈S: C, 63.86; H, 5.74; S, 6.09. Found: C, 64.08; H, 5.77; S,6.09.

Example 69

4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acryloyl)-benzoicacid

Ex-69A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.62 g,2.39 mmol) and thioacetamide (0.18 g, 2.39 mmol) in ethanol (30 mL) wasrefluxed for 2 hours and the solvent was removed under reduced pressure.The product, 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole (0.56 g, 100%)was obtained as a white solid and used without further purification. Toa suspension of 4-3,4-dimethoxy-phenyl)-2-methyl-thiazole obtained above(0.70 g, 2.97 mmol) in dichloromethane (60 mL) at 0° C. was addeddichloromethyl methyl ether (0.40 mL, 4.46 mmol) followed by addition oftitanium tetrachloride (1.0 M solution in dichloromethane, 8.9 mL, 8.9mmol) dropwise. The reaction mixture was allowed to stir overnight atambient temperature and then poured into ice. The aqueous solution wasextracted with dichloromethane. The solution of dichloromethane waswashed with hydrochloric acid (0.5M), saturated solution of sodiumbicarbonate and brine, dried over sodium sulfate and concentrated. Theproduct, 2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde, wasobtained as a white solid. ¹H NMR (CDCl₃) δ 10.33 (s, 1H), 8.67 (s, 1H),7.56 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 2.75 (s, 3H).

The title compound was prepared by condensing2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde (Ex-69A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp 201-202° C. (dec.). ¹H-NMR (DMSO-d₆) δ 8.47 (s, 1H), 8.14-7.97(m, 5H), 7.76 (s, 1H), 7.65 (d, J=15.8 Hz, 1H), 6.81 (s, 1H), 4.00 (s,3H), 3.98 (s, 3H), 2.69 (s, 3H). MS m/z=409 (M+, 70%), 378 ([M−OCH₃]⁺,100%).

Example 70

4-{3E-[5-(1H-Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid

Ex-70A: A solution of benzene-1,2-diamine (2.60 g, 24.1 mmol) and2,4-dimethoxy-benzaldehyde (4.0 g, 24.1 mmol) in ethanol (60 mL)containing catalytic amount of acetic acid was refluxed overnight.Solvent was then evaporated under reduced pressure. The residue oil wastriturated in ethyl acetate to obtain2-2,4-dimethoxy-phenyl)-1H-benzoimidazole (0.76 g, 12%). The crudeproduct was used without further purification. To a solution of2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole obtained above (0.76 g, 2.99mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether(0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride(11.0M in dichloromethane, 9.0 mL, 9.0 mmol) at 0° C. The reactionmixture was allowed to stir overnight at ambient temperature and thenpoured into ice. A solution of sodium hydroxide (5M) was added dropwiseuntil the pH of the solution was about 12. The basic solution wasextracted with dichloromethane. The combined solution of dichloromethanewas subsequently washed with brine, dried over sodium carbonate andconcentrated. The product,5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (0.40 g, 47%), wasobtain and used without further purification. ¹H NMR (CDCl₃) δ 10.32 (s,1H), 10.27 (bs, 1H), 9.03 (s, 1H), 7.83 (d, J=9 Hz, 1H), 7.48-7.45 (m,1H), 7.31-7.22 (m, 1H), 6.58 (s, 1H), 4.18 (s, 3H), 4.01 (s, 3H). MSm/z=282 (M+, 100%).

The title compound was prepared by condensing5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-70A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, mp>240° C. (dec.). ¹H-NMR (DMSO-d₆) 88.72 (s, 1H), 12.10 (s, 1H),8.18 (d, J=8.4 Hz, 2H), 8.08-8.02 (m, 3H), 7.80 (d, J=15.4 Hz, 1H), 7.59(s, 2H), 7.17-7.13 (m, 2H), 6.89 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H). MSm/z=429 ([M+H]⁺, 100%).

Example 71

4-[3E-(2-Carbamoylmethoxy4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-71A: 2-2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetamide wasprepared in an analogous fashion as described in Ex-29C using2-bromoacetamide. Silica gel chromatography (ethyl acetate/hexanes, 8:1)gave the expected product as a pale yellow solid (75%), mp: 178-179° C.¹H-NMR (300 MHz, CDCl₃) δ 10.05 (s, 1H), 7.99 (s, 1H), 7.67 (brs, 1H),7.44 (d, 1H, J=3.6 Hz), 7.34 (d, 1H, J=5.4 Hz), 7.10 (dd, 1H, J=5.4, 3.6Hz), 6.48 (s, 1H), 5.67 (brs, 1H), 4.64 (s, 2H), 4.02 (s, 3H). MS (EI)m/z=291 ([M]⁺, 100%). Anal. Calcd. for C₁₄H₁₃NO₄S: C, 57.72; H, 4.50; N,4.81; S, 11.01. Found: C, 57.63; H, 4.50; N, 4.87; S, 11.03.

The title compound was prepared by condensing2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetamide (Ex-71A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, 70% yield, mp 235° C. (dec.). ¹H-NMR (300 MHz, DMSO-d₆) δ8.26-8.30 (m, 3H), 8.08-8.11 (m, 4H) 7.67 (d, 1H, J=2.7 Hz), 7.65 (brs,1H), 7.53 (d, 1H, J=4.0 Hz), 7.49 (brs, 1H), 7.13 (m, 1H), 6.77 (s, 1H),4.75 (s, 2H), 3.97 (s, 3H). MS (EI) m/z=437 ([M]⁺, 100%). HRMS (EI)Calcd. for C₂₃H₁₉NO₆S: 437.0933. Found: 437.0924.

Example 72

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid

Ex-72A:4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-benzaldehydewas prepared in an analogous fashion as described in Ex-29C using4-(2-chloroacetyl)morpholine. Silica gel chromatography (80% ethylacetate/hexanes to 100% ethyl acetate) gave the expected product as apale yellow solid, mp 200-201° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.33 (s,1H), 8.12 (s, 1H), 7.44 (d, 1H, J=3.6 Hz), 7.31 (d, 1H, J=5.1 Hz), 7.08(dd, 1H, J=5.1, 3.6 Hz), 6.74 (s, 1H), 4.89 (s, 2H), 4.00 (s, 3H), 3.67(brs, 8H). MS (ESI) m/z=362 ([M+H]⁺, 100%). Anal. Calcd. for C₁₈H₁₉NO₅S:C, 59.82; H. 5.30; N, 3.88; S, 8.87. Found: C, 59.88; H, 5.36; N, 3.90;S, 8.75.

The title compound was prepared by condensing4-methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-benzaldehyde(Ex-72A) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Orange solid, mp 231-233° C., 70% yield. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.28-8.35 (m, 3H), 8.21 (s, 1H), 8.07-8.11 (m, 3H), 7.66 (d, 1H, J=3.3Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd 1H, J=5.1, 3.3 Hz), 6.87 (s, 1H),5.13 (s, 2H), 4.00 (s, 3H), 3.65 (brm, 4H), 3.54-3.55 (m, 4H). MS (EI)m/z=507 ([M]⁺, 1100%). Anal. Calcd. for C₂₇H₂₅NO₇S.½EtOH: C, 63.55; H,5.61; N, 2.60; S, 5.95. Found: C, 63.13; H. 5.55; N, 2.53; S, 5.84.

Example 73

4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicacid, hydrochloride

Ex-73A: Methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl esterwas prepared in an analogous fashion as described in Ex-50A using(S)-(−)-1-methyl-2-pyrrolidinemethanol. The crude orange oil was driedin vacuo to give the expected product and was used without any furtherpurification (40%). ¹H-NMR, (300 MHz, CDCl₃) δ 4.99-5.04 (m, 1H),4.41-4.51 (m, 1H), 4.19-4.29 (m, 1H), 3.88-3.94 (m, 1H), 3.49 (s, 3H),3.17-3.29 (m, 1H), 2.95-3.05 (m, 1H), 2.74 (s, 3H), 2.41-2.58 (m, 3H),1.98-2.08 (m, 2H). MS (EI) m/z.=207 ([M]⁺, 100%). HRMS (EI) Calcd. forC₁₈H₁₉NO₅S: 207.0929. Found: 207.0922.

Ex-73B:4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-benzaldehydewas prepared in an analogous fashion as described in Ex-29C usingMethanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester (Ex-73A).Silica gel chromatography (10% methanol/methylene chloride to 15%methanol/methylene chloride) gave 0.50 g (70. %) of the expected productas a pale yellow oil. ¹H-NMR (300 MHz, CDCl₃, major isomer) δ 10.35 (s,1H), 8.09 (s, 1H), 7.42-7.44 (m, 1H), 7.30 (d, 1H, J=5.1 Hz), 7.06-7.09(m, 1H), 6.49 (s, 1H), 4.80 (m, 1H), 4.20-4.26 (m, 1H), 3.98 (s, 3H),2.64-2.84 (m, 2H), 2.47 (s, 3H), 1.80-2.33 (m, 7H). MS (EI) m/z=345([M]⁺, 100%). HRMS (EI) Calcd. for C₁₈H₁₉NO₅S: 345.1399. Found:345.1401.

The title compound was prepared by condensing4-methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-benzaldehyde(Ex-73B) and 4-acetylbenzoic acid in a similar manner as described inEx-3. Dark Yellow solid, 52%, mp 206-208° C. ¹H-NMR (300 MHz, DMSO-d₆,major isomer) δ 8.30 (s, 1H), 8.25 (d, 2H, J=7.8 Hz), 8.07-8.12 (m, 3H),7.94 (d, 1H, J=15.6 Hz), 7.68 (d, 1H, J=3.3 Hz), 7.52 (d, 1H, J=5.1 Hz),7.14 (dd, 1H, J=5.1, 3.3 Hz), 6.86 (s, 1H), 5.05 (m, 1H), 4.34 (m, 1H),4.00 (s, 3H), 3.40-3.46 (m, 2H), 2.81 (s, 3H), 2.40-2.44 (m, 1H),2.16-2.27 (m, 2H), 1.81-2.00 (m, 4H). MS (ESI) m/z=492 ([M+H]⁺, 100%).Anal. Calcd. for C₂₈H₃₀ClNO₅S.½H₂O: C, 60.59; H, 5.99; N, 2.52; S, 5.78.Found: C, 60.70; H, 5.85; N, 2.64; S, 6.15.

Example 74

4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid

Ex-74A: A solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.33 g,1.70 mmol) and di-tert-butyl dicarbonate (0.51 g, 2.34 mmol) indichloromethane (10 mL) was allowed to stir overnight at ambienttemperature. The solution was then washed with saturated solution ofsodium bicarbonate and brine, dried over sodium sulfate, andconcentrated. The crude product of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (0.61 g) was used in next step without furtherpurification.

Ex-74B: To a mixture of 2,4-dimethoxy-5-bromo-benzaldehye (0.28 g, 1.13mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (Ex-76A, 0.61 g, 1.70 mmol),bis(tri-tert-butylphosphine)palladium (43 mg, 0.085 mmol) and potassiumfluoride (0.24 g, 4.08 mmol) was added degassed tetrahydrofuran (15 mL).The reaction mixture was heated at 60° C. for one day. Additionalpotassium fluoride (0.24 g, 4.08 mmol) and water (20 μL) were added. Thereaction mixture continued to stir at 60° C. for another 8 hours. Thereaction was then quenched by water. The aqueous solution was extractedwith ethyl acetate. The solution of ethyl acetate was washed withsaturated solution of sodium bicarbonate, brine, dried over sodiumsulfate and concentrated. The crude product was purified by flashchromatography. Elution with ethyl acetate (50%, v/v, in hexane)afforded 4-5-formyl-2,4-dimethoxy-phenyl)-pyrazole-1-carboxylic acidtert-butyl ester (0.15 g, 40%) as white solid. ¹H NMR (CDCl₃) δ 10.35(s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 6.52 (s, 1H), 4.02(s, 3H), 3.99 (s, 3H), 1.68 (s, 9H). MS m/z=333 ([M+H]⁺, 100%).

The title compound was prepared by condensing2,4dimethoxy-5-(1H-pyrazol-4-yl)-benzaldehyde (Ex-74B) and4-acetylbenzoic acid in a similar manner as described in Ex-3 includingan acid work-up. Yellow solid, mp>250° C. ¹H-NMR (DMSO-d₆) δ 12.42 (bs,1H), 8.20-8.03 (m, 8H), 7.85 (d, J=16.1 Hz), 6.74 (s, 1H), 3.95 (s, 3H),3.94 (s, 3H). MS m/z 379 ([M+H]⁺, 100%).

Example 75

4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid

Ex-75A: A solution of 2-(5-bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane(Ex-46A, 1.16 g, 4.9 mmol), sodium azide (641.3 mg, 9.86), and zincbromide (552.2 mg, 2.46 mmol) in water (14 mL) and isopropanol (17 mL)were mixed and refluxed for 18 hours. The reaction mixture was quenchedwith 3N HCl (60 mL) and extracted with ethyl acetate (2×75 mL). Theorganic ws concentrated to a white solid. The solid was stirred in 0.25NNaOH (100 mL) for one hour. The suspension was filtered and the filtratewas collected and acidified with 1N HCl to a pH of 2. The aqueoussolution was extracted with ethyl acetate:THF (40%). The organics werecollected and concentrated to a crude brown solid of2,4-dimethoxy-5-(2H-tetrazol-5-yl)-benzaldehyde (77.8 mg, 7%). ¹H-NMR(DMSO-d₆) δ 10.09 (s, 1H), 7.97 (s, 1H), 6.89 (s, 1H), 4.04 (s, 3H),4.02 (s, 3H). MS m/z=234 ([M]⁺, 94%), 191 (100%).

The title compound was prepared by condensing2,4-dimethoxy-5-(2H-tetrazol-5-yl)-benzaldehyde (Ex-75A) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, 19% yield, mp 218° C. (dec). ¹H-NMR (DMSO-d₆) 8.58 (s, 1H), 8.20(d, 2H), 8.03 (m, 3H), 7.85 (d, 1H), 6.90 (s, 1H), 4.04 (s, 3H), 4.02(s, 3H). MS m/z=422 ([M+CH₃CN+H]⁺, 100%). HRMS m/z: calc. 381.1199,found 381.1184.

Example 76

4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid

Ex-76A: To a suspension of 2,4-dimethoxybenzoic acid (0.36 g, 2 mmol)and 8 ml of POCl₃ in a 50 ml of a round-bottom flask,2,3-diaminopyridine (0.22 g, 2 mmol) was added. The mixture was heatedto reflux for 4 hours and then cooled to room temperature. The reactionmixture was then concentrated to remove most of the POCl₃. The residuewas carefully treated with 1N HCl at 0° C. using a water-ice bath, thenneutralized with NaOH (50%). The off-white solid was filtered to give2-(2,4-dimethoxy-phenyl)-3H-imidazo[4,5-b]pyridine (0.44 g, 88%). ¹H-NMR(DMSO-d₆) δ 8.28-8.36 (m, 2H), 7.97 (d, J=8 Hz, 1H), 7.21-7.25(m, 1H),6.80 (s, 1H), 6.78 (d, J=9 Hz, 1H), 4.05(s, 3H), 3.91 (s, 3H). HRMS(ES+) Calcd. for C₂₄H₁₉N₃O₅: 430.1403. Found: 430.1414.

Ex-76B: To a suspension of2-2,4-dimethoxy-phenyl)-3H-imidazo[4,5-b]pyridine (0.44 g, 1.7 mmol) in20 ml of CH₂Cl₂, 1,1-dichlorodimethyl ether (0.55 g, 4.8 mmol) wasadded. The mixture was cooled to 0° C. with a water-ice bath, and 7 ml(7 mmol) of TiCl₄ (1.0 m in CH₂Cl₂) was added dropwise. The mixture wasstirred at 0° C. for 2 hrs, then room temperature for overnight. Thereaction mixture was poured into ice-water and the precipitate wasfiltered to give 0.31 g (63%) of5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde as a whitesolid. ¹H-NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.67(s, 1H), 8.56 (d, J=5 Hz,1H), 8.44 (d, J=8 Hz, 1H), 7.57-7.61 (m, 1H), 6.97 (s, 1H), 4.19(s, 3H),4.06 (s, 3H). HMRS (EI) calcd. for C₁₅H₃N₃O₃: 283.0957; found: 283.0952.

The title compound was prepared by condensing5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76B)and 4-acetylbenzoic acid in a similar manner as described in Ex-3.Yellow solid, mp 222-224° C., 60% yield. ¹H-NMR (DMSO-4) δ 8.75 (s, 1H),8.38-8.40 (m, 1H), 8.18 (d, J=9 Hz, 2H), 7.99-8.08(m, 4H), 7.83(d, J=15Hz, 1H), 7.28-7.33(m, 1H), 6.91 (s, 1H), 4.11(s, 3H), 4.04 (s, 3H). MSm/z=430 ([M+H]⁺).

Example 77

2-{4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-methyl-propionicacid

Ex-77A: To a mixture of aluminum chloride (2.8 g, 20.8 mmol) in carbondisulfide (50 mL) was added acetyl chloride (0.74 mL, 10.4 mmol)followed by addition of 2-methyl-2-phenyl- propionic acid ethyl ester(1.0 g, 5.2 mmol). The reaction mixture was refluxed for 2 hours andthen poured into ice containing sulfuric acid (6M, The mixture waspartitioned. The aqueous layer was extracted with ethyl acetate. Thesolution of ethyl acetate was washed with hydrochloric acid (0.5M),saturated solution of sodium bicarbonate and brine, dried over sodiumsulfate and concentrated. The crude product was purified by flashchromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave2-(4-acetyl-phenyl)-2-methyl-propionic acid ethyl ester (0.57 g, 470 %).¹H NMR (CDCl₃) δ 7.92 (d, J=7.6 Hz, 2H), 7.42 (d, J=7.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.18 (t,J=7.2 Hz, 3H).

The title compound was prepared by condensing2-4-acetyl-phenyl)-2-methyl-propionic acid (Ex-77A) and2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manneras described in Ex-3. White foam. ¹H-NMR (CCDl₃) δ 8.11-7.86 (m, 5H),7.62-7.46 (m, 3H), 7.42 (d, J=3.2 Hz, 1H), 7.31 (d, J=5.3, 1H),7.10-7.08 (m, 1H), 6.54 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.67 (s,3H), 1.65 (s, 3H). MS m/z=436 (M⁺, 55%), 405 ([M−OCH₃]+, 100%).

Example 78

3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl-1-[4-(2H-tetrazol-5-yl)-phenyl]-propenone

Ex-78A: A suspension of 4-acetylbenznitrile (2.9 g, 20.0 mmol), sodiumazide (1.43 g, 22.0 mmol) and zinc bromide (4.5 g, 20.0 mmol) in water(50 mL) was refluxed for one day. Additional water (40 mL), HCl (3M, 30mL) and EtOAc (200 mL) were added subsequently. The mixture was stirreduntil no solid in the aqueous layer. The mixture was then portioned. Theaqueous solution was further extracted with EtOAc (3×60 mL). Thecombined EtOAc was concentrated. The residue was treated with NaOH (0.25M, 200 mL). After stirred for 50 min, insoluble material was filtered,washed with NaOH (1M). The filtrate was then acidified with HCl (conc.)to pH 3. The resulting white precipitate was filtered, washed with waterand dried in vacuo to obtain 1-[4-(2H-tetrazol-5-yl)-phenyl]-ethanone aswhite solid. ¹H NMR (DMSO-d₆) δ 8.17-8.10 (m, 4H), 2.6-[(s, 3H). MSm/z=188 (M⁺).

The title compound was prepared by condensing1-[4-(2H-tetrazol-5-yl)-phenyl]-ethanone (Ex-78A) and2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manneras described in Ex-3. Yellow solid, mp 2350C (dec.). ¹H-NMR (DMSO-d₆) δ8.33 (d, J=8.4 Hz, 2H), 8.26 (s, 1H), 8.20 (d, J=8.9 Hz, 2H), 8.08 (d,J=16.0 Hz, 1H), 7.93 (d, J=15.0 Hz, 1H), 7.66-7.64 (m, 1H), 7.50-7.48(m, 1H), 7.12-7.09 (m, 1H), 6.81 (s, 1H), 3.983 (s, 3H), 3.976 (s, 3H).MS m/z=418 (M⁺, 100%).

Example 79

4-[3Z-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid

A solution of4-[3E-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid(Ex-3, 101.4 mg, 0.23 mmol) in ethyl acetate (889 ml) was stirred in awell lighted-area at room temperature for 36 hours. The solution wasconcentrated to a yellow solid. The crude material was purified onreversed-phase preprative plates (20×20 cm, RP-18 F₂₅₄, 1 mm) elutedwith MEOH/ACN/H₂O (45:45:10) to give 22.2 mg of the title compound,which was 86% the cis isomer by NMR analysis. ¹H-NMR (DMSO-D₆, majorisomer) δ 7.98 (s, 4H), 7.86 (m, 2H), 7.76 (d, J=9 Hz 1H), 7.56 (s, 1H),7.28 (m, 2H), 7.17 (d, J=12 Hz, 1H), 6.78 (d, J=12 Hz, 2H), 6.71 (s,1H), 3.94 (s, 3H), 3.77 (s, 3H).

Example 80

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide

To a solution of 4-acetyl-benzsulfonamide (Ex-26A, 0.20 g, 1.0 mmol) and5-benzo[b]thiophene-2-yl-2,4-dimethoxyphenylbenzaldehyde (Ex-3A, 0.31 g,1.05 mmol) in DMF (5 mL) and methanol (2 mL) was added lithium methoxide(0.15 g, 4.0 mmol). The reaction mixture was allowed to stir at ambienttemperature. The reaction was quenched with water (30 mL) after 2 hours.The aqueous solution was acidified to pH 4 with HCl (3 M) and extractedwith ethyl acetate. The combined solution of ethyl acetate wassubsequently washed with brine, dried (Na₂SO₄) and concentrated. Thesolid residue was stirred in ethanol (10 mL) for 1.5 hours, filtered,washed with aqueous ethanol (50%) and dried in vacuo. The title compoundwas obtained as a yellow solid (0.3 g, 63%), mp 204-205° C. (dec.).¹H-NMR (DMSO-d₆) δ 8.35 (s, 1H), 8.27 (d, J=7.7 Hz, 2H), 8.06 (d, J=16.0Hz, 1H), 7.97-7.92 (m, 4H), 7.88 (d, J=6.6 Hz, 1H), 7.81 (d, J=7.4 Hz,1H), 7.53 (s, 2H), 7.37-7.27 (m, 2H), 6.85 (s, 1H), 4.09 (s, 3H), 4.03(s, 3H).

Example 81

4-(3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

4-Acetyl-benzenesulfonamide (Ex-26A) (0.10 g, 0.29 mmol) and4-acetylbenzenesulfonamide (0.057 g, 0.29 mmol) were dissolved in adimethylformamide-methanol solution (2.0 mL, 7:3). After completedissolution, lithium methoxide (0.044 g, 1.2 mmol) was added and theresulting orange slurry was stirred in the dark at room temperature for4 h. Upon completion, as determined by HPLC, the mixture was dilutedwith water (15 mL) and extracted with ethyl acetate (3×25 mL). Thecombined organic extracts were dried over sodium sulfate and1-evaporated to dryness. The crude oil was taken up in ethanol (2 mL)and warmed to 60° C. to obtain complete dissolution and allowed to coolto room temperature. The resulting precipitate was collected on filterpaper and dried in vacuo to yield 0.13 g (82%) of the title compound asa yellow solid, mp 186-188° C. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.23-8.28 (m,3H), 7.93-8.09 (m, 4H), 7.66 (d, 1H, J=3.0 Hz), 7.56 (brs, 1H), 7.52 (d,1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.0 Hz), 6.89 (s, 1H), 4.34 (t, 2H,J=6 Hz), 4.01 (s, 3H), 3.543.58 (m, 4H), 2.83 (t, 2H, J=6 Hz), 2.51-2.53(m, 4H). MS (ESI) m/z=529 ([M+H]⁺, 100%). Anal. Calcd. for C₂₆H₂₈N₂O₆S₂:C, 59.07; H, 5.34; N, 5.30; S, 12.13. Found: C, 58.90; H, 5.38; N, 5.37;S, 12.01.

Example 82

2-{5Methoxy-2-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-thiophen-2-yl-phenoxy}-2-methyl-propionicacid

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid(Ex-59B) in a similar manner as described in Ex-22. Yellow solid, mp164-165° C., 85% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.21-8.28 (m, 3H),7.96-8.12 (m, 4H), 7.67 (d, 1H, J=3.0 Hz), 7.56 (brs, 3.0H), 7.14 (dd,1H, J=5.7, 3.0 Hz), 6.57 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI)m/z=502 ([M+H]⁺, 100%). Anal. Calcd. for C₂₄H₂₃NO₇S₂: C, 57.47; H, 4.62;N, 2.79; S, 12.79. Found: C, 57.70; H, 4.74; N, 2.85; S, 12.51.

Example 83

2-{2,4-Dimethoxy-5-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-phenyl}-indole-1-carboxylicacid tert-butyl ester

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and2-(5-formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butylester (Ex-36A) in a similar manner as described in Ex-22. Yellow solid,40% yield, mp 120-122° C. ¹H-NMR (CDCl₃) δ 8.01-8.19 (m, 6H), 7.68 (s,1H), 7.56 (d, J=8 Hz, 1H), 7.46(d, J=16 Hz, 1H), 7.21-7.35(m, 2H), 6.53(d, J=14 Hz, 2H), 5.01(s, 2H), 4.00 (s, 3H), 3.85(s, 3H), 1.42 (s, 9H).MS m/z=563 ([M+H]⁺). HRMS (ES+) Calcd. for C₃₀H₃₀N₂O₇S: 563.1852. Found:563.1862.

Example 84

4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-61A) in a similarmanner as described in Ex-22. Red solid, 70% yield, mp 185-187° C.¹H-NMR (DMSO-0.4) δ 11.15 (br, s, 1H), 8.33(s, 1H), 8.24 (d, J=8 Hz,2H), 8.07 (d, J=15 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.80(d, J=15 Hz, 1H),7.41-7.55(m, 4H), 7.03-7.08 (m, 1H), 6.936.99 (m, 2H), 6.83 (s, 1H),4.04(s, 3H), 3.99(s, 3H). MS m/z=463 ([M+H]⁺). HRMS (ES+) Calcd. forC₂₅H₂₂N₂O₅S: 463.1327. Found: 463.1316.

Example 85

4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde(Ex-46A) in a similar manner as described in Ex-22. Yellow solid, 48%yield, mp 193-196° C. ¹H-NMR (DMSO-d6) δ 8.24 (m, 3H), 8.06 (s, 1H),7.96 (d, 2H), 7.89 (d, 1H), 7.63 (d, 1H), 7.51 (m, 1H), 7.10 (dd, J=3, 4Hz, 1H), 6.81 (s, 1H), 4.23 (t, 2H), 3.98(s, 3H), 3.55 (t, 4H), 2.47 (m,2H), 2.35(t, 4H), 1.98(q, 2H). MS m/z=542 ([M]⁺, 38%), 100 (100%). Anal.calculated for C₂₇H₃₀N₂O₆S₂.⅗H₂O: C, 58.59; H, 5.68; S, 11.59; found C,58.59; H, 5.55; S, 11.40.

Example 86

4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-64B) (8.0 g, 24.8 mmol) and 4-acetylbenzenesulfonamide (4.9 g, 24.8mmol) were dissolved in a dimethylformamide-methanol solution (170 mL,7:3). After complete dissolution, lithium methoxide (3.8 g, 99.2 mmol)was added and the resulting red-orange slurry was stirred in the dark atroom temperature for 3 h. Upon completion, as determined by HPLC, themixture was diluted with water (500 mL) and extracted with ethyl acetate(6×200 mL). The combined organic extracts were dried over sodium sulfateand evaporated to dryness. The crude oil was taken up in ethanol (150mL) and warmed to 60° C. to obtain complete dissolution and allowed tocool to room temperature. The resulting precipitate was collected onfilter paper and dried in vacuo to yield 7.0 g (60%) of the titlecompound as a light orange solid, mp 123-124° C. ¹H-NMR (300 MHz,DMSO-d₆) δ 8.25-8.29 (m, 3H), 7.90-8.11 (m, 4H), 7.66 (d, 1H, J=3.0 Hz),7.56 (brs, 1H), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.0 Hz),6.88 (s, 1H), 4.67 (t, 2H, J=10.8 Hz), 4.24 (d, 2H, J=6.0 Hz), 4.00 (s,3H), 3.54-3.65 (m, 4H), 2.09-2.13 (m, 1H). MS (ESI) m/z=504 ([M+H]⁺,100%). Anal. Calcd. C₂₄H₂₅NO₇S₂H₂O: C, 57.24; H, 5.00; N, 2.78; S,12.73. Found: C, 56.72; H, 5.27; N, 2.71; S, 12.11.

Example 87

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-isobutryl-benzenesulfonamide

A solution of4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide(Ex-80, 0:15 g, 0.31 mmol) in tetrahydrofuran (3 mL) was cooled to −78°C. and a solution of lithium bis(trimethylsilyl)amide (1.0 M intetrahydrofuran, 0.63 mL, 0.63 mmol) was added dropwise. The solutionwas allowed to stir at this temperature for 1 hour and warm up to 0° C.Isobutyric acid anhydride (0.31 mL, 1.88 mmol) was added at thistemperature. The solution was allowed to stir at 0° C. for 10 min andambient temperature for 2 hours. The reaction then was quenched withwater. The aqueous solution was extracted with ethyl acetate. Thecombined solution of ethyl acetate was washed with brine, dried oversodium sulfate and concentrated. The residual material was stirred inethanol for 3 hours, filtered and dried in vacuo to give the titlecompound as a yellow solid (0.15 g, 87%), mp>240° C. (dec.). ¹H-NMR(CDCl₃) δ 8.21 (d, J=8.6 Hz, 2H), 8.13 (d, J=8.7 Hz, 2H), 8.09 (s, 1H),8.02 (bs, 1H), 7.94 (s, 1H), 7.85-7.78 (m, 2H), 7.68 (s, 1H), 7.55 (d,J=16.9 Hz, 1H), 7.38-7.30 (m, 2H), 6.58 (s, 1H), 4.04 (s, 3H), 4.01 (s,3H), 2.47-2.38 (m, 1H), 1.14 (d, J=7.1 Hz, 6H). MS m/z=549 (M⁺, 100%).

Example 88

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide,hydrochloride

Th4{3-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide(Ex-81, 0.065 g, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL) and3 N HCl (1 mL) was added drop wise to the solution. The resulting yellowslurry was stirred in the dark at room temperature for 30 min. Theprecipitate was collected and dried in vacuo to yield 0.054 g (78%) ofthe title compound as a yellow solid, mp 235° C. (dec). ¹H-NMR (300 MHz,DMSO-d₆): δ 8.31-8.34 (m, 3H), 8.13 (d, 1H, J=15.0 Hz), 7.92-8.01 (m,3H), 7.70 (d, 1H, J=4.0 Hz), 7.54 (m, 3H), 7.15-7.17 (m, 1H), 6.92 (s,1H), 4.64 (brs, 2H), 4.03 (s, 5H), 3.72-3.79 (m, 4H), 3.56-3.60 (m, 4H).MS (ESI) m/z=529 ([M+H]⁺, 100%). Anal. Calcd. for C₂₆H₂₉ClN₂O₆S₂: C,55.26; H, 5.17; Cl, 6.27; N, 4.96; S, 11.35. Found: C, 55.31; H, 5.17;Cl, 6.32; N, 4.98; S, 11.20.

Example 89

4-{3E-[4-Methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

Ex-89A: (2-Acetyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetonitrile wasprepared in an analogous fashion as described in Ex-29C usingiodoacetonitrile. The crude solid was slurried in ethyl acetate (50 mL)to remove residual impurities. The resulting solid was collected onfilter paper and dried in vacuo to give the expected product as anorange solid (70%), mp 175-176° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.29 (s,1H), 8.17 (s, 1H), 7.48 (d, 1H, J=3.6 Hz), 7.35 (d, 1H, J=5.1 Hz), 7.10(dd, 1H, J=5.1, 3.6 Hz), 6.64 (s, 1H), 4.96 (s, 2H), 4.06 (s, 3H). MS(EI) m/z=273 ([M]⁺, 99%), 233 (100%). Anal. Calcd. for C₁₄H₁₁NO₃S: C,61.52; H, 4.06; N, 5.12; S, 11.73. Found: C, 61.65; H, 4.20; N, 5.16; S,11.59.

Ex-89B: (2-Acetyl-5-methoxy-4-thiophen-2-yl-phenoxy)acetonitrile(Ex-89A, 0.30 g, 1.1 mmol) was slurried in a mixture ofwater:isopropanol (3 mL, 2:1) to obtain a well-dispersed solution.Sodium azide (0.079 g, 1.2 mmol) followed by zinc bromide (0.25 g, 1.1mmol) were added and the reaction was heated to reflux and vigorouslystirred for 24 h. Additional solvent (1 mL, 1:1 water:isopropanol) wasadded after 10 h at reflux due to evaporation. The reaction was dilutedwith an ethyl acetate:tetrahydrofuran mixture (25 mL, 2:1) and a 3 N HClsolution (10 mL) and vigorously stirred until a homogenous solution wasobtained (1 h). The layers were separated and the aqueous was extractedwith ethyl acetate (3×50 mL). The combined organic extracts were driedover sodium sulfate and concentrated to a dark green solid. Silica gelchromatography (15% methanol/methylene chloride containing 1% aceticacid) gave 0.22 g (65%) of4-methoxy-2-(1H-tetrazol-5-ylmethoxy)₅-thiophen-2-yl-benzaldehyde as apale green solid. ¹H-NMR (300 MHz, DMSO-d₆). 10.33 (s, 114), 7.97 (s,1H), 7.52-7.56 (m, 2H), 7.10-7.12 (m, 2H), 5.81 (s, 2H), 4.05 (s, 3H).MS (ESI) m/z=317 ([M+H]⁺, 100%). HRMS (ESI) Calcd. for C₂₇H₂₅NO₇S:317.0708. Found: 317.0712.

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and4-methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-benzaldehyde(Ex-89A) in a similar manner as described in Ex-22. Yellow solid, mp163-164° C. (dec), 60% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.31-8.34 (m,3H), 7.92-8.15 (m, 4H), 7.70 (d, 1H, J=4.0 Hz), 7.54 (m, 3H), 7.15-7.17(m, 1H), 6.92 (s, 1H), 4.64 (brs, 2H), 4.03 (s, 5H). MS (ESI) m/z=498([M+H]⁺, 100%). Anal. Calcd. for C₂₂H₁₉N₅O₅S₂-11/2H₂O: C, 50.37; H,4.23; N, 13.35; S, 12.23. Found: C, 50.48; H. 4.24; N, 12.95; S, 12.35.

Example 90

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-(2-morpholin-4-yl-ethyl)-benzamide

To a solution of4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid(Ex-3, 0.44 mg, 1 mmol) and 2-morpholin-4-ylethylamine (0.18 mL) indichloromethane (20 mL) was added13-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2mmol) and the mixture was stirred at room temperature for four hours. Itwas poured into brine (100 mL) and extracted with dichloromethane (2×50mL). The organic phase was dried and evaporated. Chromatography(dichloromethane/methanol 50:1) gave the title compound as a yellowsolid (0.43 g, 77%). ¹H-NMR (300 MHz, CDCl₃) δ 8.12 (d, J=16 Hz, 1H),8.09 (d, J=8 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J=8 Hz, 2H), 7.77-7.85 (m,2H), 7.68 (s, 1H), 7.56 (d, J=16 Hz, 1H), 7.29-7.40 (m, 2H), 6.80-6.85(br s, 1H), 6.58 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H), 3.75 (t, J=5 Hz,4H), 3.59 (quad, J=5 Hz, 2H), 2.64 (t, J=5 Hz, 2H), 2.53 (t, J=5 Hz,4H). Anal. calc. for C₃₂H₃₂N₂O₅S.H₂O: C, 67.94; H, 5.88; N, 4.95; found:C, 68.12; H, 5.92; N, 4.96.

Example 91

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-(2,2,2-trifluoro-ethyl)-benzamide

The title compound was prepared in a similar manner as described inEx-90. Yellow solid, 53% yield, mp 215-217° C. ¹H-NMR (Aceton-d₆) δ 8.46(br, s, H), 8.12-8.24 (m, 4H), 8.06 (d, J=8 Hz, 2H), 7.78-7.91 (m, 4H),7.28-7.36(m, 2H), 6.92(s, 1H), 4.08 (s, 3H), 4.06(s, 3H), 2.79 (s, 2H).MS m/z=526 ([M+H]⁺). HRMS (ES+) Calcd. for C₂₈H₂₂F₃NO₄S: 526.1300.Found: 526.1324.

Example 92

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzamide

Ex-92A: To a solution of 4-acetyl-benzoic acid (0.5 g, 3.05 mmol) intetrahydrofuran (10 mL) was added carbonyldiimidazole (0.74 g, 4.75mmol). The solution was allowed to stir at ambient temperature for onehour and cooled to 0° C. followed by addition of ammonia (28% in water,3 mL, 21 mmol). The solution was continued to stir at 0° C. for anotherone hour. The solvent was removed under reduced pressure. The residuewas treated with water, filtered, washed with water, dried in vacuo togive 4-acetyl-benzamide (0.25 g, 50%) as a white solid. ¹H NMR (DMSO-d₆)δ 8.11 (bs, 1H), 8.00 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 7.53 (bs,1H), 2.59 (s, 3H).

To a solution of 4-acetyl-benzamide (Ex-92A, 0.25 g, 1.53 mmol) and2-(2-morpholin-4-yl-ethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-60A, 0.53 g, 1.53 mmol) in DMF (7 mL) and methanol (3 mL) was addedlithium methoxide. The solution was allowed to stir at ambienttemperature. The reaction was quenched with water after 2 hours. Theaqueous solution was extracted with ethyl acetate. The combined extractwas washed with NaHCO₃, NH₄Cl, brine, dried (Na₂SO₄) and concentrated.The residue was stirred in ethanol overnight to afford the titlecompound as a yellow solid (0.43 g, 57%), mp 183-1840C. ¹H-NMR (CDCl₃) δ8.09-8.04 (m, 3H), 7.93 (d, J=8.3 Hz, 2H), 7.87 (s, 1H), 7.57 (d, J=15.7Hz, 1H), 7.42 (d, J=3.9 Hz, 1H), 7.32 (d, 4.4 Hz, 1H), 7.11-7.08 (m,1H), 6.55 (s, 1H), 6.25 (bs, 1H), 5.75 (bs, 1H), 4.25 (t, J=5.9 Hz, 2H),3.98 (s, 3H), 3.71 (t, J=4.2 Hz, 4H), 2.92 (t, J=5.7 Hz, 2H), 2.59 (t,J=4.6 Hz, 4H). MS m/z=493 ([M+H]⁺, 100%).

Example 93

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4dimethoxy-phenyl)-acryloyl]-benzamide

To a solution of 4-acetyl-benzamide (0.3 g, 1.84 mmol) and5-(benzo[b]thein-2yl)-2,4-dimethoxybenzaldehyde (0.55 g, 1.84 mmol) in amixture of N,N-dimethylformamide (7 mL) and methanol (3 mL) was addedlithium methoxide (0.14 g, 3.68 mmol). The reaction mixture was allowedto stir at ambient temperature for 9 hours. The resulting precipitatewas collected by filtration, washed with methanol, dried in vacuo toobtain the title compound as a yellow solid (5.56 g, 68%).Alternatively, to mixture of4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid (Ex-3, 3.0 g, 6.75 mmol),1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.81 g, 9.45mmol), 1-hydroxybenzotriazole hydrate (1.09 g, 8.10 mmol) and ammoniumchloride (1.81 g, 33.7 mmol) in N,N-dimethylformamide (60 mL) was addedtriethylamine (2.4 mL, 16.9 mmol). The reaction mixture was allowed tostir overnight at ambient temperature. Any insoluble material wasremoved by filtration. The filtrate was diluted with ethyl acetate to180 mL. The solution of ethyl acetate was washed with a saturatedsolution of sodium bicarbonate, brine, dried over sodium sulfate andconcentrated to give the title compound as a yellow solid (2.82 g, 94%),mp 240-241-C. ¹H-NMR (DMSO-d₆) δ 8.37 (s, 1H), 8.19 (d, J=7.8 Hz, 2H),8.12 (d, J=15.3 Hz, 1H), 8.04-7.91 (m, 6H), 7.83 (d, J=7.5 Hz, 1H), 7.55(s, 1H), 7.36-7.30 (m, 2H), 6.87 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). MSm/z=444 ([M+H]⁺, 100%).

Example 94

4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzamide

The title compound was prepared by condensing 4-Acetyl-benzamide(Ex-92A) and4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde(Ex-66A) in a similar manner as described in Ex-92. Orange solid, mp81-83° C. ¹H-NMR (CDCl₃) δ 8.08 (m, 3H), 7.94 (d, 2H), 7.86 (s, 1H),7.56 (d, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.10 (m, 1H), 6.55 (s, 1H),4.19 (t, 2H), 3.99(s, 3H), 3.72 (t, 4H), 2.59 (t, 2H), 2.12 (t, 4H),1.98(quintet, 2H). MS m/z=506 ([M]⁺, 34%), 100 (100%). 28%. Anal.calculated for C₂₉H₃₀N₂O₅S.⅖H₂O: C, 65.45; H, 6.04; S, 6.24; found C,65.30; H, 6.16; S, 6.17.

Example 95

N-Acetyl-4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide

A suspension of4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide(Ex-93, 0.5 g, 1.13 mmol) in THF (15 mL) was cooled to −78° C. followedby addition of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.3 mL,2.3 mmol). The mixture was stirred at this temperature for 1 hour andwarmed up to 0° C. Acetic anhydride (0.48 mL, 6.8 mmol) was then addeddropwise. After the addition was complete the reaction mixture waswarmed up to ambient temperature and stirred for 2 hours. The reactionwas quenched with water. The aqueous solution was extracted with ethylacetate. The combined extract was washed with NH₄Cl, brine, dried andconcentrated. The residue was purified by flash chromatography. Elutionwith 50% EtOAc/hexane gave the title compound as yellow solid (0.16 g,29%), mp 228-229° C. ¹H-NMR (CCDl₃) δ 8.52 (s, 1H), 8.15-8.10 (m, 3H),7.96 (d, J=7.6 Hz, 2H), 7.85-7.77 (m, 2H), 7.67 (s, 1H), 7.55 (d, J=16.7Hz, 1H), 7.34-7.29 (m, 3H), 6.58 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H),2.65 (s, 3H). MS m/z=485 (M+, 100%).

Example 96

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl-benzamide

The title compound was prepared in a similar manner as described inEx-95 from-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)acryloyl]-benzamide(Ex-93) and isobutyric anhydride. Yellow solid, mp 208-209° C. ¹H-NMR(CCDl₃) δ 8.14 (s, 1H), 8.15-8.10 (m, 3H), 7.96 (d, J=^(7.2) Hz, 2H),7.85-7.77 (m, 2H), 7.67 (s, 1H), 7.56 (d, J=16.2 Hz, 1H), 7.38-7.29 (m,3H); 6.59 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.68-3.59 (m, 1H), 1.28(d, J=6.2 Hz, 6H).: MS m/z=513 (M⁺, 93%), 425 (100%).

Example 97

4(3E-{4-[3-(4-Thiophen-2-yl-phenyl)acryloyl]-phenyl}-ureido)-acetic acid

A solution of(3-{4-[3-(4-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-ureido)-acetic acidethyl ester (Ex-15, 151.3 mg, 0.35 mmol) in THF:MeOH:H₂O (2:1:1, 6 mL)was treated with lithium monohydrate (73.2 mg, 1.74 mmol) and stirredfor 4 hours. The reaction mixture was titrated with 5N HCl to a pH2. Themixture was extracted with ethyl acetate (30 mL). The organic phase wascollected, dried over Na₂SO₄, and concentrated to a pure yellow solid(131.7 mg, 93%), mp 222-225° C. ¹H-NMR (DMSO-d₆) δ 9.27 (br s, 1H), 8.14(d, 2H), 7.87 (m, 3H), 7.71 (d, 3H), 7.56 (m, 4H), 7.14 (t, 1H), 6.54(t, 1H), 3.78 (d, 2H). MS m/z=407 ([M+H]⁺, 88%), 306 (100%). Anal.calculated for C₂₂H₁₈N₂O₄S.½H₂O: C, 63.60; H, 4.61; S, 7.72; found C,63.23; H, 4.70; S, 7.66.

Example 98

N-{4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-N-methyl-methanesulfonamide

A solution ofN-{4-[3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-methanesulfonamide(Ex-14, 90 mg, 0.20 mmol) in anhydrous DMF was treated with potassiumcarbonate (56.1 mg, 0.41). Methyl iodide (126.32 uL, 2.03 mmol) wasadded to the reaction mixture which was then refluxed for 1.5 hoursunder inert conditions. The reaction was diluted with water (25 mL) andextracted with diethyl ether (2×50 mL). The organic portion was driedover sodium sulfate, filtered, and concentrated to a yellow oil. Thecrude material was purified by silica gel chromatography (30-50% ethylacetate/hexanes) to give 42 mg (45%) of the title compound as a yellowsolid. ¹H-NMR (CDCl₃) δ 8.06 (d, 2H), 7.59 (d, 1H), 7.54 (m, 4H), 7.42(m, 2H), 7.12 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.40 (s, 3H), 2.89(s, 3H). MS m/z=457 ([M]⁺, 100%).

Example 99

3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-1-1-[4-(D-glucopyranosylamino)-phenyl]-propenone

Ex-99A: D-Glucose (1.8 g, 10 mmol) and 4-aminoacetophenone (1.35 g, 10mmol) were mixed in ethanol (50 ml), acetic acid (5 drops) was added,and the mixture was stirred at reflux for 2 hours. Water (2 ml) wasadded and the mixture became a homogeneous solution and was then stirredat reflux for 4 hours. Upon cooling to room temperature the precipitatewas filtered out, rinsed with ethanol, and dried to give4-(D-glucopyranosylamino)acetophenone as a white solid (1.21 g, 41%), mp209-210C (dec). ¹H-NMR (DMSO-D₆) δ 7.71 (d, J=8 Hz, 2H), 7.06 (d, J=8Hz, 1H), 6.69 (d, J=8 Hz, 2H), 4.98 (d, J=4 Hz, 1H), 4.89 (d, J=7 Hz,2H), 4.384.45 (m, 2H), 3.55-3.64 (m, 1H), 3.30-3.46 (m, 1H), 3.00-3.30(m, 4H), 2.38 (s, 3H). MS m/z=297 ([M]⁺, 15%), 148 (100%).

4-(D-Glucopyranosylamino)acetophenone (Ex-99A, 326 mg, 0.6 mmol) and(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A, 150 mg, 0.5 mmol)were mixed in DMF (10 ml) and methanol (5 ml). Lithium methoxide (120mg) was added, and the mixture was stirred at room temperature for 18hours. Lithium methoxide (120 mg) was added again and the mixture wasstirred overnight. Saturated sodium chloride solution (50 ml) was addedand the mixture was extracted with dichloromethane. Chromatography(dichloromethane/methanol 10:1) gave an oily yellow residue as the titlecompound (20 mg, 6%). ¹H-NMR (DMSO-D₆) δ 8.29 (s, 1H), 7.78-8.02 (m,7H), 7.25-7.38 (m, 2H), 7.15 (d, 1H), 6.84 (s, 1H), 6.77 (d, 2H), 4.99(d, 1H), 4.86-4.95 (m, 2H), 4.41-4.49 (m, 2H), 4.02 (s, 3H), 3.98 (s,3H), 3.00-3.45 (m 6H). MS m/z=578 ([M+H]⁺, 100%).

Example 100

2-{4-[3-(4-Methanesulfonylamino-phenyl)-3-oxo-E-propenyl]-5-methoxy-2-thiophen-2-yl-phenoxy})-2-methyl-propionicacid

Ex-100A: A solution of 4-aminoacetophenone (5.0 g, 37.0 mmol) andpyridine (3.0 mL) in anhydrous dichloromethane (300 mL) was treated withmesyl chloride (2.86 mL, 37.0 mmol). The reaction was stirred for 84hours at room temperature under nitrogen, and then quenched withsaturated NH₄Cl solution (100 mL). The organic phase was collected,washed with water (100 mL) and brine, dried over sodium sulfate, andconcentrated over silica. The material was purified by silica gelchromatography (50% ethyl acetate/hexanes) to give 4.72 g (60%) ofN-(4-acetyl-phenyl)methanesulfonamide as a yellowish oil. ¹H-NMR(DMSO-d₆) δ 10.28 (s, 1H), 7.90 (d, 1H), 7.24 (d, 1H), 3.06 (s, 3H),2.48 (s, 3H).

A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 279.6 mg,1.31 mmol) and2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid(Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) wastreated with lithium methoxide (182.2 mg, 4.8 mmol) and stirred for 5hours at room temp. under nitrogen atmosphere. The reaction mixture wasdiluted with water (25 mL) which was then extracted with isopropylacetate (2×50 mL). The aqueous portion was collected and acidified to apH of 3 with 3N HCl. The aqueous solution was then extracted withisopropyl acetate (2×50 mL). The organic was collected, dried oversodium sulfate, and concentrated to a green solid. Attempted torecrystallize crude material from ethanol/hexanes; however, this mixturewas concentrated and stirred with ethyl acetate (3 mL) to give 95.6 mg(14%) of the title compound as a yellow solid, mp 181-183° C. ¹H-NMR(DMSO-d₆) δ 10.31 (br s, ¹H), 8.24 (s, 1H), 8.12 (d, 2H), 7.95 (d, 1H),7.87 (d, 1H), 7.67 (d, 1H), 7.50 (d, 1H), 7.30 (d, 2H), 7.09 (t, 1H),6.45 (s, 1H), 3.81 (s, 3H), 3.08 (s, 3H), 1.65 (s, 6H). MS m/z=516([M+H]⁺, 100%). HRMS m/z: calc. 516.1150, found 516.1165.

Example 101

2-(4-{3-[4-(Methanesulfonyl-methyl-amino)-phenyl]-3-oxo-E-propenyl}-5methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid

Ex-101A: A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A,2.0 g, 9.4 mmol) in anhydrous DMF (300 mL) was treated with potassiumcarbonate (2.59 g, 18.8 mmol), followed by the addition of methyl iodide(5.85 mL, 94 mmol). The reaction mixture refluxed for two hours and wasthen treated with more methyl iodide (5.85 mL, 94 mmol). The reactionrefluxed for another two hours, and reaction completeness was confirmedby HPLC analysis. The reaction was quenched with water (100 mL) andextracted with ethyl acetate (2×100 mL). The organic phase wascollected, dried over sodium sulfate, and concentrated to a clear oilwith residual DMF. Water (25 mL) was added to precipitate a white solid.The white solid was then filtered and dried by vacuum oven at 20° C.(−20 mm Hg) to give 1.37 g (64%) ofN-(4-acetyl-phenyl)-N-methyl-methanesulfonamide. ¹H-NMR (CDCl₃) δ 7.88(d, 2H), 7.48 (d, 2H), 3.38 (s, 3H), 2.86 (s, 3), 2.60 (s, 3H). HRMSm/z; calc. 530.1307, found 530.1313.

A solution of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide (Ex-101A,298 mg, 1.31 mmol) and2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid(Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) wastreated with lithium methoxide (182 mg, 4.8 mmol) and stirred for 6hours at room temperature under nitrogen atmosphere. The reactionmixture was diluted with water (25 mL) which was then extracted withisopropyl acetate (2×50 mL). The aqueous portion was collected andacidified to a pH of 3 with 3N HCl. The aqueous solution was thenextracted with isopropyl acetate (2×50 mL).

The organic was collected, dried over sodium sulfate, and concentratedto a yellow foam. The crude material was purified by silica gelchromatography (50% ethyl acetate/hexanes; 10% MeOH/CH₂CL₂) to give 293mg (42%) of the title compound as a yellow solid, mp 197-200° C. ¹H-NMR(DMSO-d₆) δ 8.20 (s, 1H), 8.12 (d, 2H), 8.00 (d, 1H), 7.83 (d, 1H), 7.66(dd, J=2,2 Hz, 1H), 7.53 (d, 2H), 7.44 (d, 1H), 7.06 (dd, J=2,4 Hz, 1H),6.78 (s, 1H), 3.82 (s, 3H), 3.28 (s, 3H), 2.98 (s, 3H), 1.56 (s, 3H). MSm/z 530 ([M+H]⁺, 100%).

Example 102

3-Amino-4-{4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)acryloyl]-phenylamino}-cyclobut-3-ene-1,2-dione

Ex-102A: To a solution of 2.7 g (20 mmol) of 4′-aminoacetophenone in 90mL of ethanol, 4.5 g (20 mmol) of 3,4-dibutoxy-3-cyclobutene-1,2-dione(Aldrich) was added. The mixture was then heated to reflux overnight. Alight yellow precipitate formed. To the reaction mixture, 20 mL (40mmol) of ammonia (2.0 M in ethanol) was added, and the resultant mixturewas stirred at room temperature for 2 hr. The light yellow solid wasfiltered and washed with ethanol to give 2.4 g (52%) of3-(4-acetyl-phenylamino)-4-amino-cyclobut-3-ene-1,2-dione. ¹H-NMR(DMSO-d₆) δ 9.99 (br, 1H), 7.90 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H),4.31 (br, 2H), 2.48 (s, 3H). HMRS (EI) calcd. for C₁₂H₁₀N₂O₃: 230.0691;found: 230.0691.

3-(4-Acetyl-phenylamino)-4-amino-cyclobut-3-ene-1,2-dione (Ex-102A, 0.46g, 2 mmol), and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A,0.596 g, 2 mmol) were dissolved in DMF (10 mL) under nitrogen, and 4.0ml (4 mmol) of LiOMe (1.0 M in MeOH) was added.

The mixture was stirred under nitrogen at room temperature over night.The reaction mixture was poured into ice-water, acidified to pH1 with 3NHCl, extracted with dichloromethane. The combined organic phase was thenwashed with brine and water, dried over MgSO₄, column chromatography (5%MeOH in CH₂Cl₂) to give 57 mg (5.4%) title compound as a yellow solid,mp>260° C. ¹H-NMR (DMSO-d₆) δ 10.08 (s, 1H), 8.36 (s, 1H), 8.18 (d, J=8Hz, 2H), 8.03 (d, J=15 Hz, 1H), 7.82-7.95 (m, 4H), 7.57 (d, J=8 Hz, 2H),7.27-7.37 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.26 (s,2H). MS m/z=511[M+H]⁺, (20%), 416 (100%). HRMS (ES+) Calcd. forC₂₉H₂₂N₂O₅S: 511.1327. Found: 511.1326.

Example 103

5-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzo[1,3]dioxole-2,2-dicarboxylicacid, diethyl ester

Ex-103A: To a solution of KOH (1.25 M, 200 mL) were added3,4-dihydroxy-acetophenone (2.0 g, 13.1 mmol) and cetyltrimethylamoniumchloride (25% in water, 17 mL, 13.1 mmol). The suspension was stirred atambient temperature for 10 min followed by the addition of a suspensionof 3,4-dimethoxy-5-thiophen-2yl-benzaldehyde (Ex-4A, 3.9 g, 15.8 mmol)in ethanol (10 mL). The reaction mixture was allowed to stir at ambienttemperature overnight and was acidified with concentrated HCl to pH 3,saturated with NaCl, extracted with CH₂Cl₂. The combined solution ofCH₂Cl₂ was washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by flashchromatography. Elution with 50% EtOAc/hexane gave1-3,4-dihydroxy-phenyl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-propenone as a yellow oil. ¹H NMR (DMSO-d₆) δ 7.88 (s, 1H),7.83-7.81 (m, 2H), 7.76 (d, J=2.4 Hz, 1H), 7.68-7.74 (m, 2H), 7.61-7.57(m, 1H), 7.51 (s, 1H), 7.50 (d, J=5.2 Hz, 1H), 7.13 (t, J=4.5 Hz, 114),6.85 (d, J=8.7 Hz, 1H), 3.92 (s, 3H), 3.77 (s, 3H). MS m/z=382 (M⁺,100%).

1-(3,4-Dihydroxy-phenyl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-propenone(106 mg), diethyl dibromomalonate (380 mg) and potassium carbonate (500mg) was mixed in acetone (15 ml) and the mixture was stirred at roomtemperature over a weekend. It was poured into ethyl acetate (100 ml)and washed with water (100 ml). The organic layer was dried andevaporated. Chromatography (hexanes/ethyl acetate 4:1) gave an oilyresidue. Crystallization from hexanes and dichloromethane gave the titlecompound as a slightly yellow solid (70 mg), mp 125-126° C. ¹H-NMR(DMSO-d₆) δ 7.76 (d, J=15 Hz, 1H), 7.73 (dd, J=2, 7 Hz, 1H), 7.64 (d,J=2 Hz, 1H), 7.54 (d, J=1 Hz, 1H), 7.53 (d, J=2 Hz, 1H), 7.39 (d, J=5Hz, 1H), 7.38 (d, J=15 Hz, 1H), 7.11 (dd, J=2, 5 Hz, 1H), 7.08 (d, J=1Hz, 1H), 7.05 (d, J=7 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 4.41 (quad,J=7 Hz, 4H), 1.30 (t, J=7 Hz, 6H).

Example 104

4-[3E-(2,4-Dimethoxy-5-pyridin-3-yl-phenyl)-acryloyl]-benzenesulfonamide

Ex-104A: 2,4-Dimethoxy-5-pyridin-3-yl-benzaldehyde was prepared in asimilar manner as described in Ex-3A from pyridine-3-boronic acid and5-bromo-2,4-dimethoxybenzaldehyde, 68% yield. ¹H-NMR (CDCl₃) δ 10.33 (s,1H), 8.71 (d, J=1 Hz, 1H), 8.51-8.53(m, 1H), 7.81 (s, 1H), 7.74-7.78 (m,1H), 7.27-7.31 i (m, 1H), 6.52 (s, 1H), 3.99 (s, 3H), 3.91 (s, 3H). HMRS(EI) calcd. for C₁₄H₁₃NO₃: 243.0895; found: 243.0888.

The title compound was prepared by condensing2,4-dimethoxy-5-pyridin-3-yl-benzaldehyde (Ex-104A) and4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described inEx-22. Yellow solid, 51% yield, mp 253-255° C. ¹H-NMR (DMSO-d₆) δ 8.69(d, J=1 Hz, 1H), 8.50 (d, J=4 Hz, 1H), 8.25 (d, J=9 Hz, 2H), 8.08 (d,J=15 Hz, 1H), 8.02 (s, 1H), 7.84-7.94(m, 41-1), 7.51 (s, 2H), 7.40-7.44(m, 1H), 6.82(s, 1H), 3.98 (s, 3H), 3.88 (s, 3H). MS m/z=424([M]⁺, 45%),393 (100%). HMRS (EI) calcd. for C₂₂H₂₀N₂O₅S: 424.1093; found: 424.1100.

Example 105

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid, hydrochloride

Ex-105A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.3 g,1.16 mmol), cyclopropanecarboxamidine (0.14 g, 1.16 mmol) and sodiumhydroxide (0.18 g, 4.5 mmol) in ethanol was refluxed overnight. Thesolvent was removed under reduced pressure, the residue taken up towater. The aqueous solution was then extracted with dichloromethanewhich was subsequently washed with brine, dried over sodium bicarbonateand concentrated. The crude product was purified by flashchromatography. Elution with ethyl acetate (50%, v/v, in hexane) thenmethanol (10%, v/v in dichloromethane) afforded2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H-imidazole as white solid (0.15g, 53%): ¹HNMR (CDCl₃) δ 9.50 (bs, 1H), 7.63 (s, 1H), 7.20 (s, 1H),6.57-6.53 (m, 2H), 3.93 (s, 3H), 3.03 (s, 3H), 1.97-1.93 (m, 1H),1.00-0.94 (m, 4H). MS m/z=245 ([M+H]⁺, 100%).

Ex-105B: To a solution of2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H-imidazole (0.51 g, 2.09 mmol)was added dichloromethyl methyl ether (0.28 mL, 3.13 mmol) followed byaddition of titanium tetrachloride (11.0M in dichloromethane, 8.4 mL,8.4 mmol) dropwise at 0° C. The solution was allowed to warm up toambient temperature and stir for 4.5 hours. The reaction mixture wasthen poured into ice. The aqueous layer was adjusted to pH 12 andextracted with dichloromethane. The combined solution of dichloromethanewas washed with saturated solution of sodium bicarbonate, brine, driedover sodium sulfate and concentrated to afford5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde which wasused without further purification. ¹H NMR (DMSO-d₆) δ 13.95 (bs, 1H),10.22 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 6.88 (s, 1H), 4.04 (s, 3H),4.00 (s, 3H), 2.25 (m, 1H), 1.20 (m, 4H). MS m/z=245 ([M+H]⁺, 100%).

The title compound was prepared by condensing 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-105B) and4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellowsolid, m.p.>240° C. ¹H NMR (DMSO-d₆) δ 13.31 (bs, 1H), 8.29 (d, J=8.9Hz, 2H), 8.06-8.01 (m, 3H), 7.91 (s, 1H), 7.67 (s, 1H), 6.83 (s, 1H),4.02 (s, 3H), 3.98 (s, 3H), 1.29-1.22 (m, 4H). MS m/z=419 ([M+H]⁺,100%).

Example 106

4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

The title compound was prepared by condensing4-3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-50C) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner asdescribed in Ex-22. Yellow solid, 72% yield, mp 191-192° C. ¹H-NMR (300MHz, DMSO-d₆) δ 8.29-8.32 (m, 3H), 8.09 (d, 1H, J=16.0 Hz), 7.99 (d, 2H,J=8.1 Hz),; 7.92 (d, 1H, J=16.0 Hz), 7.70 (d, 1H, J=3.3 Hz), 7.53-7.56(m, 3H), 7.14 (dd, 1H, J=5.4, 3.3 Hz), 6.87 (s, 1H), 4.61 (t, 2H, J=5.1Hz), 4.28 (d, 2H, J=5.1 Hz), 4.00 (s, 3H), 3.60-3.67 (m, 4H), 2.11-2.15(m, 1H). MS (ESI) m/z=504 ([M+H]⁺, 100%). Anal. Calcd. forC₂₄H₂₅NO₇S₂.½H₂O: C, 56.23; H. 5.11; N, 2.73; S, 12.51. Found: C, 56.32;H, 5.06; N, 2.83; S, 12.55.

Example 107

1-(4-Benzenesulfonyl-phenyl)-3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-propenone

The title compound was prepared by condensing1-(4-benzenesulfonyl-phenyl)-ethanone with5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A) in a similarmanner as described in Ex-3, 5% yield. The product was purified usingcolumn chromatography. Yellow solid, mp 127-128° C. ¹H-NMR (CDCl₃) δ8.05-8.11 (m, 5H), 7.97 (d, J=7 Hz, 2H), 7.91 (s, 1H), 7.76-7.84 (m,2H), 7.66 (s, 1H), 7.46-7.60(m, 4H), 7.26-7.37(m, 2H), 6.56(s, 1H), 4.03(s, 3H), 3.99 (s, 3H). MS m/z=540 ([M]⁺, 100%). HRMS (EI) Calcd. forC₁₃H₂₄O₅S₂: 540.1605. Found: 540.1074.

Example 108

1-(4-Acetyl-phenyl)-3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-propenone

The title compound was prepared by condensing1-(4-acetyl-phenyl)-ethanone with5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A) in a similarmanner as described in Ex-3. The product was purified using columnchromatography. Yellow solid, 2% yield, mp 165-167° C. ¹H-NMR (CDCl₃) δ8.06-8.12 (m, 5H), 7.92 (s, 1H), 7.75-7.82 (m, 2H), 7.65 (s, H), 7.55(d, J=15 Hz, 1H), 7.28-7.33(m, 2H), 6.56(s, 1H), 4.01 (s, 3H), 3.98 (s,3H). MS m/z=442 ([M]⁺, 100%). HMRS (EI) calcd. for C₂₇H₂₂O₄S: 442.1239;found: 442.1229.

Example 109

4-{3E-[5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide

Ex-109A: A solution of 2,4-dimethoxy-benzoic acid methyl ester (4.24 g,21.6 mmol) and hydrazine (3.4 mL, 108.1 mmol) in methanol (50 mL) wasrefluxed overnight. Solvent was removed under reduced pressure. Theresidue was re-dissolved in ethyl acetate. The solution of ethyl acetatewas washed with saturated solution of sodium bicarbonate and brine,dried over sodium carbonate and concentrated to afford2,4-dimethoxy-benzoic acid hydrazide (3.31 g, 78%) as a white solid: ¹HNMR (CDCl₃) δ 8.77 (bs, 1H), 8.15 (d, J=8.8 Hz, 1H), 6.58 (dd, J=8.8,2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 4.10 (bs, 2H), 3.91 (s, 3H), 3.83(s, 3H).

Ex-109B: A solution of 2,4-dimethoxy-benzoic acid hydrazide (Ex-109A,1.0 g, 5.1 mmol) and isobutyl-isothiocyanate (0.70 g, 6.1 mmol) inethanol (30 mL) was refluxed for 8 hours. The precipitate was filtered,washed with ethanol, dried in vacuo to afford1-(2,4-dimethoxy-benzoyl)amino-3-isobutyl-thiourea (1.43 g). Additionalproduct (0.1 g, 96% overall) was obtained by concentrating the motherliquid. ¹H NMR (CDCl₃) δ 10.71 (bs, 1H), 9.23 (bs, 1H), 8.03 (d, J=8.6Hz, 1H), 6.98 (bs, 1H), 6.59 (dd, J=8.6, 2.6 Hz, 1H), 6.51 (d, J=2.6 Hz,1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.41 (dd, J=6.4, 6.6 Hz, 2H), 1.96-1.87(m, 1H), 0.91 (d, J=6.5 Hz, 6H).

Ex-109C: A solution of1-(2,4-dimethoxy-benzoyl)amino-3-isobutyl-thiourea (Ex-109B, 0.5 g, 1.61mmol) and sodium hydroxide (0.999M, 4.8 mL, 4.8 mmol) in ethanol (30 mL)was refluxed for one day. The solvent was removed under reduced pressureand the residue re-dissolved in ethyl acetate. The solution of ethylacetate was washed with water and brine, dried over sodium sulfate, andconcentrated to give 5-(2,4-dimethoxy-phenyl)isobutyl-4H-[1,2,4]triazole-3-thiol (0.1 g). Additional product (0.36 g,98% overall) was obtained by extracting the water wash withdichloromethane and a mixture of isopropyl alcohol (33%, v/v, indichloromethane). ¹H NMR (CDCl₃) δ 10.82 (bs, 1H), 7.24 (d, J=. 8.1 Hz,1H), 6.56 (dd, J=8.1, 2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.85 (s, 3H),3.77 (s, 3H), 3.72 (d, J=6.7 Hz, 2H), 2.17-2.08 (m, 1H), 0.70 (d, J=6.7Hz, 6H).

Ex-109D: To a solution of5-2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole-3-thiol (Ex-109C,0.1 g, 0.34 mmol) in ethanol (10 mL) was added wet Raney Ni (0.27 g, 4.6mmol). The suspension of ethanol was refluxed overnight and then passedthrough a bed of Hyflo Super Gel and diatomaceous earth. The filtratewas concentrated to afford 3-(2,4-dimethoxy-phenyl)4-isobutyl-4H-[1,2,4]triazole (0.09 g, 100%) as a white solid: ¹H NMR(CDCl₃) δ 8.15 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 6.57 (dd, J=7.8, 2.3 Hz,1H), 6.51 (d, J=2.3 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.62 (d, J=7.5Hz, 2H), 1.89-1.80 (m, 1H), 0.76 (d, J=6.6 Hz, 6H).

Ex-109E: To a solution of3-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole (Ex-109D, 0.78 g,2.98 mmol) was added dichloromethyl methyl ether (0.4 mL, 4.48 mmol)followed by addition of titanium tetrachloride (11.0M indichloromethane, 9.0 mL, 9.0 mmol) over 10 min at 0° C. The reactionmixture was allowed to stir at 0° C. for 30 min and ambient temperatureovernight. The reaction mixture was poured into ice. The aqueoussolution was extracted with dichloromethane and isopropyl alcohol (33%,v/v, in dichloromethane). The combined dichloromethane and isopropylalcohol were washed with brine, dried over sodium sulfate andconcentrated. The aqueous solution was treated with sodium hydroxide topH 12 and extracted again with isopropyl alcohol (33%, v/v, indichloromethane) to give additional product. The crude product waspurified by flash chromatography. Elution with methanol (10%, v/v, indichloromethane) afford5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (0.24g, 28%): ¹HNMR (CDCl₃) δ 10.30 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 6.51(s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 3.58 (d, J=7.2 Hz, 2H), 1.91-1.80(m, 1H), 0.77 (d, J=6.5 Hz, 6H).

To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12 g, 0.62 mmol)and 5-4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde(Ex-109E, 0.18 g, 0.62 mmol) in N,N-dimethylformamide (9 mL) was addedlithium methoxide (11.0M in methanol, 2.4 mL, 2.4 mmol). The solutionwas allowed to stir overnight. The reaction was quenched with water. Theaqueous solution was washed ethyl acetate, acidified to pH 5, extractedwith dichloromethane, isopropyl alcohol (33%, v/v, in dichloromethane).The combined dichloromethane and isopropyl alcohol was washed withbrine, dried over sodium sulfate and concentrated. The crude product wasthen stirred in ethanol (50%, v/v, in acetone) to give the titlecompound as a light yellow solid: m.p.>240° C. ¹H NMR (DMSO-d₆) δ 8.60(s, 1H), 8.26 (d, J=8.1 Hz, 2H), 8.06 (d, J=15.3 Hz, 1H), 8.07 (s, 1H),7.91 (d, J=8.1 Hz, 2H), 7.84 (d, J=15.3 Hz, 1H), 7.50 (s, 1H), 6.84 (s,1H), 4.01 (s, 3H), 3.87 (s, 3H), 3.61 (d, J=7.3 Hz, 2H), 1.81-1.74 (m,1H), 0.67 (d, J=16.7 Hz, 6H). MS m/z=471 ([M+H]⁺, 100%).

Example 110

4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid

To a solution of 4-acetyl-benzoic acid (0.12 g, 0.75 mmol) and5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde(Ex-109E, 0.24 g, 0.83 mmol) in N,N-dimethylformamide (6 mL) was addedlithium methoxide (11.0M in methanol, 3.0mL, 3.0 mmol). The solution wasallowed to stir overnight and additional lithium methoxide (0.11 g, 2.8mmol). The reaction was quenched with water after 20 hours. The aqueoussolution was washed ethyl acetate, acidified to pH 4. The precipitatewas filtered, washed with ethanol and dried in vacuo to afford the titlecompound as a light yellow solid: m.p.>240° C. (dec.). ¹H NMR (DMSO-d₆)δ 8.59 (s, 1H), 8.18 (d, J=7.9 Hz, 2H), 8.07 (s, 1H), 8.04-8.01 (m, 3H),7.85 (d, J=15.7 Hz, 1H), 6.84 (s, 1H), 4.06 (s, 3H), 3.92 (s, 3H), 3.66(d, J=7.2 Hz, 2H), 1.87-1.74 (m, 1H), 0.72 (d, J=6.7 Hz, 6H). MS m/z=436([M+H]⁺, 100%).

Example 111

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide

To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12 g, 0.59 mmol)and 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde(Ex-105B, 0.16 g, 0.59 mmol) in N,N-dimethylformamide (16 mL) was addedlithium methoxide (11.0M in methanol, 2.4 mL, 2.4 mmol). The reactionmixture was allowed to stir for 18 hours at ambient temperature. Thereaction was quenched with water. The aqueous solution was extractedwith dichloromethane. The combined dichloromethane was concentrated. Thecrude product was purified by flash chromatography. Elution withmethanol (10%, v/v, in dichloromethane) gave the title compound as redsolid: m.p. 156-160° C. ¹H NMR (DMSO-d₆) δ 11.65 (bs, 1H), 8.32 (s, 1H),8.19 (d, J=9.0 Hz, 2H), 8.00 (d, J=15.7 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H),7.62-7.52 (m, 2H), 7.24 (bs, 1H), 6.73 (s, 1H), 3.96 (s, 3H), 3.94 (s,3H), 1.98-1.94 (m, 1H), 0.88-0.85 (m, 4H). MS m/z=454 ([M+H]⁺, 100%).

Example 112

4-(3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl)-benzenesulfonamide

The title compound was prepared by condensing5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76A)with 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner asdescribed in Ex-22. Yellow solid, 26% yield, mp>260° C. ¹H-NMR (DMSO-d₆)δ 8.73 (s, 1H), 8.31 (dd, J=1, 4 Hz, 1H), 8.26 (d, J=8 Hz, 2H), 8.05(d,J=16 Hz, 1H), 7.89-7.97 (m, 3H), 7.82(d, J=16 Hz, 1H), 7.17-7.21(m, 1H),6.89(s, 1H), 4.09 (s, 3H), 4.03 (s, 3H). MS m/z=465([M+H]⁺, 65%), 256(100%). HRMS (ES+) Calcd. for C₂₃H₂₀N₄O₅S: 465.1232. Found: 465.1240.

Example 113

4-{3E-[2-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

Ex-113A:2-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehydewas prepared in a similar manner as described in Ex-29C. Off-whitesolid, 67% yield, mp 230° C. (dec). ¹H-NMR (300 MHz, DMSO-d₆) □ 10.44(s, 1H), 8.00 (s, 1H), 7.79-7.84 (m, 2H), 7.49-7.57 (m, 4H), 7.16 (s,1H), 7.12 (dd, 1H, J=5.4, 3.6 Hz), 5.91 (s, 2H), 4.07 (s, 3H). MS (ESI)m/z=365 ([M+H]⁺, 100%). Anal. Calcd. for C₂₀H₁₇ClN₂O₃S.⅓H₂O: C, 59.04;H, 4.38; N, 6.88; S, 7.88. Found: C, 59.07; H, 4.25; N,. 0.77.

The title compound was prepared by condensing2-(1H-benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-113A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manneras described in Ex-22. Light orange solid, 56% yield, mp 235-237° C.(dec). ¹H-NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.19 (d, 2H, J=8.4 Hz),8.11 (d, 1H, J=15.4 Hz), 7.98 (d, 1H, J=15.4 Hz), 7.89 (d, 2H, J=8.4Hz), 7.66-7.70 (m, 3H), 7.53-7.55 (m, 3H), 7.22-7.27 (m, 2H), 7.12-7.15(m, 2H), 5.59 (s, 2H), 4.01 (s, 3H). MS (ESI) m/z=546 ([M+H]⁺, 100%).Anal. Calcd. for C₂₈H₂₃N₃O₅S₂: C, 61.64; H, 4.25; N, 7.70; S, 11.75.Found: C, 61.49; H, 4.47; N, 7.74; S, 11.58.

Example 114

4-{3E-[4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl)-benzenesulfonamide

Ex-114A: 4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-benzaldehydewas prepared in a similar manner as described in Ex-29C. Yellow solid,93% yield, mp 93-94° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.49 (s, 1H), 8.62(d, 1H, J=5.1 Hz), 8.13 (s, 1H), 7.77 (dt, 1H, J=7.5, 1.5 Hz), 7.58 (d,1H, J=7.5 Hz), 7.44 (dd, 1H, J=3.6, 1.5 Hz), 7.28-7.31 (m, 2H), 7.07(dd, 1H, J=5.4, 3.6 Hz), 6.64 (s, 1H), 5.39 (s, 2H), 3.94 (s, 3H). MS(ESI) m/z=326 ([M+H]⁺, 100%). Anal. Calcd. for C₁₈H₁₅NO₃S: C, 66.44; H,4.65; N, 4.30; S, 9.85. Found: C, 66.43; H, 4.72; N, 4.37; S, 9.81.

The title compound was prepared by condensing4-methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-114A)and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner asdescribed in Ex-22. Yellow solid, 90% yield, mp 188-189° C. ¹H-NMR (300MHz, DMSO-d₆)δ 8.66 (d, 1H, J=3.6 Hz), 8.28(s, 1H), 8.21 (d, 2H, J=7.8Hz), 8.11 (d, 1H, J=15.4 Hz), 7.89-7.99 (m, 4H), 7.57-7.68 (m, 4H), 7.53(dd, 1H, J=5.4, 1.5 Hz), 7.41-7.45 (m, 1H), 7.13 (dd, 1H, J=5.4, 3.6Hz), 7.02 (s, 1H), 5.45 (s, 2H), 3.99 (s, 3H). MS (ESI) m/z=507 ([M+H]⁺,100%). Anal. Calcd. for C₂₆H₂₂N₂O₅S₂.½H₂O: C, 60.57; H, 4.50; N, 5.43;S, 12.44. Found: C, 60.92; H, 4.54; N, 5.48; S, 12.32.

Example 115

4-{3E-[2-(Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

Ex-115A:2-Benzotriazol-1-ylmethoxy)₄-methoxy-5-thiophen-2-yl-benzaldehyde wasprepared in a similar manner as described in Ex-29C. Off-white solid,92% yield, mp 137-138° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.30 (s, 1H), 8.10(d, 1H, J=8.1 Hz), 8.06 (s, 1H), 7.75 (d, 1H, J=8.1 Hz), 7.57-7.62 (m,1H), 7.40-7.48 (m, 21), 7.30 (d, 1H, J=5.1 Hz), 7.08 (s, 1H), 7.05 (dd,1H, J=5.1, 3.6 Hz), 6.74 (s, 2H), 4.01 (s, 3H). MS (ESI) m/z=366([M+H]⁺, 100%). Anal. Calcd. for C₁₉H₁₅N₃O₃S: C, 62.45; H, 4.14; N,11.50; S, 8.78. Found: C, 62.69; H, 4.30; N, 11.52; S, 8.62.

The title compound was prepared by condensing2-(benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde(Ex-115A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manneras described in Ex-22. Light yellow solid, 56% yield, mp 255° C. (dec).1H- NMR (300 MHz, DMSO-d₆) δ 8.21 (s, 1H), 8.09 (d, 3H, J=9.4 Hz), 8.01(d, 1H, J=7.8 Hz), 7.93 (d, 2H, J=7.8 Hz), 7.75 (d, 2H, J=9.4 Hz),7.56-7.69 (m, 4H), 7.42-7.47 (m, 1H), 7.38 (s, 1H), 7.13 (dd, 1H, J=5.4,3:6 Hz), 7.05 (s, 2H), 4.05 (s, 3H). MS (ESI) m/z=547 ([M+H]⁺, 100%).Anal. Calcd. C₂₇H₂₂N₄O₅S₂: C, 59.33; H, 4.06; N, 10.25; S, 11.73. Found:C, 59.45; H, 4.27; N, 9.92; S, 11.27.

Example 116

4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzoicacid

Ex-116A: To a solution of N-methyl indole (1.3 g, 10 mmol) in 50 ml THF,t-BuLi (1.7m in THF, 7.1 ml, 12 mmol) was slowly added at 0° C. undernitrogen. The mixture was stirred at room temperature for 1 hr, BEt₃(1.0 M in THF, 12 ml, 12 mmol) was added, and the mixture stirred foranother 1 hr at room temperature. Then, PdCl₂(PPh₃)₂ (0.35 g, 0.5 mmol)and 5-bromo-2,4-dimethoxybenzaldehyde (3.7 g, 15 mmol) were added, andthe mixture was heated to about 60° C. for 30 minutes. The reactionmixture was poured into 50 ml 10% NaOH and treated with 30% H₂O₂ andthen stirred for 10 minutes. The mixture was extracted with EtOAc andcombined organic phase was washed with H₂O and brine, dried over MgSO₄,and absorbed to small amount of silica gel. Column chromatography(EtOAc:Hexane, 1:2) gave 0.72 g (25%)2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde. ¹H-NMR (CDCl₃) δ10.33 (s, 1H), 7.84 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H),7.18-7.24 (m, 1H), 7.07-7.12(m, 1H), 6.53 (s, 1H), 6.46(s, 1H), 4.00 (s,3}1), 3.89 (s, 3H), 3.53 (s, 3H). HRMS (EI) Calcd. for C₁₈H₁₇NO₃:295.1208. Found: 295.1202.

The title compound was prepared by condensing 4-acetylbenzoic acid and2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in asimilar manner as described in Ex-3. Yellow solid, 87% yield, mp157-160° C. ¹H-NMR (DMSO-d₆) δ 8.17 (d, J=8 Hz, 2H), 8.08 (d, J=15 Hz,1H), 7.99-9.02 (m 3H), 7.83 (d, J=15 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.42(d, J=8 Hz, 1H), 7.10-7.15 (m, 1H), 6.99-7.04(m, 1H), 6.85 (s, 1H),6.42(s, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 3.50 (s, 3H). MS m/z=442([M+H]⁺, 100%). HRMS (ES+) Calcd. for C₂₇H₂₃NO₅: 442.1654. Found:442.1633.

Example 117

4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzenesulfonamide

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in asimilar manner as described in Ex-3. Yellow solid, 90% yield, mp148-150° C. ¹H-NMR (CDCl₃) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz,2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d,J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22-7.26 (m, 1H), 7.11-7.16(m, 1H),6.58 (s, 1H), 6.50(s, 1H), 4.92 (br, 2H), 4.02 (s, 3H), 3.90 (s, 3H),3.58 (s, 3H). MS m/z=477 ([M+H]⁺, 100%). HRMS (ES+) Calcd. forC₂₆H₂₄NO₅S: 477.1484. Found: 477.1487.

Example 118

4-13E-5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid methyl ester

The title compound was prpared by esterification of4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid (Ex-3) with methanol in the presence of EDCI and DMAP. Yellowsolid, 34% yield, m.p. 149-151° C. ¹H-NMR (300 MHz, CDCl₃): 8.17 (d, 2H,J=6.7 Hz), 8.10 (d, 1H, J=15.8 Hz), 8.05 (d, 2H, J=6.7 Hz), 7.95 (s,1H), 7.82 (m, 2H), 7.67 (s, 1H), 7.57 (d, 1H, J=15.8 Hz), 7.33 (m, 2H),6.58 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H). MS m/z=458([M]⁺, 100%). HRMS (EI) Calcd. for C₂₇H₂₂O₅S: 458.1188. Found: 458.1196.

Example 119

4-{3-[3E-(2,3-Dihydro-furan-2-yl)-phenyl]-acryloyl}-benzenesulfonamide

Ex-119A: 5-Bromobenzaldehyde (0.5 g, 2.7 mmol) and 2,3-dihydrofuran(0.56 g, 8.1 mmol) were dissolved in dioxane (5.0 mL). Nitrogen wasbubbled into the solution for 15 min followed by the sequential additionof cesium carbonate (0.96 g, 2.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.027 mmol). The solution wasimmediately heated to 45° C. and aged for 24 h. Upon completion, asdetermined by HPLC, the reaction was diluted with water (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic extractswere dried over sodium sulfate and concentrated to a brown oil. Silicagel chromatography (ethyl acetate/hexanes, 1:9) gave 0.18 g (40%) of3-(2,3-dihydro-furan-2-yl)- benzaldehyde as a clear, colorless oil.¹H-NMR (300 MHz, CDCl₃) δ 10.03 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H,J=7.2 Hz), 7.62-7.64 (m, 1H), 7.53 (t, 1H, J=7.2 Hz), 6.48 (q, 1H,J=Hz), 5.60(dd, 1H, J=8.1, 10.8 Hz), 4.98 (q, 1H, J=3.3 Hz), 3.15 (ddt,1H, J=15.0, 8.1, 2.5 Hz), 2.59 (ddt, 1H, J=15.0, 8.1, 2.5 Hz). MS (EI)m/z=174 ([M]⁺, 100%). HRMS (EI) Calcd. for C₁₁H₁₀O₂: 174.0681. Found:174.0677.

The title compound was prepared by condensing4-acetyl-benzenesulfonamide (Ex-26A) and3-(2,3-dihydro-furan-2-yl)-benzaldehyde (Ex-119A) in a similar manner asdescribed in Ex-3.

Tan solid, 40% yield, mp 152-153° C. ¹H-NMR (300 MHz, DMSO-6)δ 8.31 (d,2H, J=7.5 Hz), 7.99 (d, 2H, J=7.5 Hz), 7.95 (d, 1H, J=15.8 Hz), 7.85(brs, 3H), 7.78 (d, 1H, J=15.8 Hz), 7.57 (brs, 1H), 7.44-7.52 (m, 2H),6.62 (q, 1H, J=2.4 Hz), 5.58 (dd, 1H, J=8.7, 10.8 Hz), 5.59(q, 1H, J=2.4Hz), 3.10 (ddt, 1H, J=15.0, 8.1, 2.5 Hz), 2.54 (ddt, 1H, J=15.0, 8.1,2.5 Hz). MS (ESI) m/z=356 ([M+H]⁺, 100%). Anal. Calcd. forC₁₉H₁₇NO₄S.⅕H₂O: C, 63.56; H, 4.89; N, 3.90; S, 8.93. Found: C, 63.64;H. 4.88; N, 4.00; S, 8.71.

Example 120

4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid,N-methyl-D-glucamine salt

4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acidof Ex. 3 was then made into a meglumine salt by suspending the4-[3E-5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid(4.45 g, 10 mmol) and N-methyl-D-glucamine (1.95 g, 10 mmol) in THF (100mL). The mixture was stirred at room temperature for 5 minutes. Then,ethanol (100 mL) was added. This mixture was stirred at room temperaturefor 30 minutes. THF (20 mL) and ethanol (20 mL) were added and themixture was heated slightly until it became a solution. This solutionwas stirred for 30 minutes and evaporated to a yellow foam.Crystallization from methanol gave the desired4-[3E-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acidN-methyl-D-glucamine salt as a yellow solid (4 g, 63%), mp 75-80° C.(changing forms). ¹H NMR (300 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.14 (d,2H), 8.02-8.10 (m, 3H), 7.94-7.98 (m, 3H), 7.86 (d, 1H), 7.36 (m, 2H),6.89 (s, 1H), 4.06 (s, 3H), 4.04 (s, 3H), 3.94 (m, 1H), 3.71 (d, 1H),3.61 (m, 1H), 3.39-3.55 (m, 3H), 3.04 (m, 1H), 2.95 (m, 1H), 2.54 (s,3H). Anal. Calculated for C₃₃H₃₇NO₁₀S.1.3H₂O: C, 59.77; H, 6.02; N,2.11; S, 4.84; found: C, 59.84; H, 5.75; N, 2.05; S, 4.70; Parent EIMSm/z=443 (M⁺).

Using the above procedure for producing the meglumine salt or procedureswell known in the art, any of the compounds of the invention can belikewise made into a hydroxylamine salt and in particular the megluminesalt.

Example 121

4-{3E-[5-(2,5-Dihydro-furan-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide

Ex-121A: 5-Bromo-2,4-dimethoxybenzaldehyde (1.0 g, 4.0 mmol) and2,3-dihydrofuran (0.85 g, 12.2 mmol) were dissolved in dioxane (10.0mL). Nitrogen was bubbled into the solution for 15 min followed by thesequential addition of cesium carbonate (1.4 g, 4.5 mmol) andbis(tri-t-butylphosphine)palladium (0) (0.021 g, 0.041 mmol). Thesolution was immediately heated to 45° C. and aged for 72 h. Additionalequivalents of cesium carbonate (0.70 g, 2.1 mmol), 2,3-dihydrofuran(0.85 g, 12.2 mmol), and Pd catalyst (0.0021 g, 0.0041 mmol) were addedafter 24 h and 48 h to drive the reaction to completion. Uponcompletion, as determined by HPLC, the reaction was diluted with water(30 mL) and extracted with ethyl acetate (3×30 mL). The combined organicextracts were dried over sodium sulfate and concentrated to an orangeoil. Silica gel chromatography (ethyl acetate/hexanes, 1:2) afforded0.32 g (50%) of 5-(2,5-dihydro-furan-2-yl)-2,4-dimethoxy-benzaldehyde asa pale yellow solid, mp 84-85° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.29 (s,1H), 7.79 (s, 1H), 6.42 (s, 1H), 5.99-6.06 (m, 2H), 5.89-5.92 (m, 1H),4.804.87 (m, 1H), 4.71-4.77 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS (EI)m/z=234 ([M]⁺, 100%). Anal. Calcd. C₁₃H₁₄O₄: C, 66.66; H, 6.02. Found:C, 66.49; H, 6.08.

5-(2,5-Dihydro-furan-2-yl)2,4-dimethoxy-benzaldehyde (Ex-121A, 0.10 g,0.43 mmol) and 4-acetylbenzenesulfonamide (Ex-26A, 0.085 g, 0.43 mmol)were dissolved in a dimethylformamide-methanol solution (2.9 mL, 7:3).After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) wasadded and the resulting orange slurry was stirred in the dark at roomtemperature for 4 h. Upon completion, as determined by HPLC, the mixturewas diluted with water (15 mL) and extracted with ethyl acetate (3×20mL). The combined organic extracts were dried over sodium sulfate andevaporated to dryness. The crude oil was taken up in ethanol (2 mL) andwarmed to 60° C. to obtain complete dissolution and allowed to cool toroom temperature. The resulting precipitate was collected on filterpaper and dried in vacuo to yield 0.13 g (70%) of the title compound asa yellow solid, mp 194-195° C. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.23 (d, 2H,J=8.2 Hz), 8.03 (d, 1H, J=15.3 Hz), 7.97 (d, 2H, J=8.2 Hz), 7.69 (s,1H), 7.65 (d, 1H, J=15.3 Hz), 7.55 (brs, 2H), 6.73 (s, 1H), 6.06-6.09(m, 1H), 5.90-5.98 (m, 2H), 4.86-4.92 (m, 1H), 4.634.68 (m, 1H), 3.96(s, 3H), 3.92 (s, 3H). MS (ESI) m/z=416 ([M+H]⁺, 100%).-Anal. Calcd.C₂₁H₂₁NO₆S: C, 60.71; H, 5.09; N, 3.37; S, 7.72. Found: C, 60.95; H,5.24; N, 3.46; S, 7.72.

Example 122

4-{3E-[4-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

Ex-122A: To a solution of2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (0.68 g, 2.9 mmol) and2-bromo-6-methylpyridine (0.25 g, 1.4 mmol) in toluene (1.0 mL) wasadded ethyl acetate (0.0063 g, 0.072 mmol, 1-naphthoic acid (0.50 g, 2.9mmol), 5A molecular sieves (0.36 g), cesium carbonate (0.94 g, 2.9mmol), and copper(I) triflate-benzene complex (0.020 g, 0.036 mmol). Thephenoxide crashed out of solution upon addition of cesium carbonate andadditional toluene (1 mL) was added to facilitate stirring. Theheterogeneous solution was immediately heated to 110° C. and aged for 24h. Upon completion, as determined by HPLC, the reaction was diluted witha 5% sodium hydroxide solution (10 mL) and ethyl acetate (10 mL) andstirred for 30 min. The layers were separated and the aqueous layer wasextracted with ethyl acetate (5×20 mL). The combined organic extractswere washed with a 50% brine solution (1×25 mL), brine (1×25 mL), driedover sodium sulfate and concentrated to an dark brown semi-solid. Silicagel chromatography (ethyl acetate/hexanes, 1:4) afforded 0.30 g (65%) of4-methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehydeas alight orange solid, mp 140-141° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.21 (s,1H), 8.23 (s, 1H), 7.64 (dd, 1H, J=7.8, 7.2 Hz), 7.52 (d, 1H, J=3.3 Hz),7.35 (d, 1H, J=5.1 Hz), 7.10 (dd, 1H, J=5.1, 3.3 Hz), 6.94 (d, 1H, J=7.2Hz), 6.78 (d, 1H, J=7.8 Hz), 6.75 (s, 1H), 3.92 (s, 3H), 2.44 (s, 3H).HRMS (EI) Calcd. for C₁₈H₁₅NO₃S: 325.0773. Found: 325.0775. Anal. Calcd.C₁₈H₁₅NO₃S: C, 66.44; H, 4.65; N, 4.30; S, 9.85. Found: C, 60.00; H,4.58; N, 4.05; S, 9.84.

4-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde(Ex-122A, 0.20 g, 0.62 mmol) and 4-acetylbenzenesulfonamide (Ex-26A,0.12 g, 0.62 mmol) were dissolved in a dimethylformamide-methanolsolution (4.2 mL, 7:3). After complete dissolution, lithium methoxide(0.093 g, 2.5 mmol) was added and the resulting orange slurry wasstirred in the dark at room temperature for 3 h. Upon completion, asdetermined by HPLC, the mixture was diluted with water (10 mL) andextracted with ethyl acetate (3×20 mL). The combined organic extractswere dried over sodium sulfate and evaporated to dryness. The crude oilwas taken up in ethanol (2 mL) and warmed to 60° C. to obtain completedissolution and allowed to cool to room temperature. The resultingprecipitate was collected on filter paper and dried in vacuo to yield0.25 g (82%) of the title compound as a yellow solid, mp 164-165° C.¹H-NMR (300 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.24 (d, 2H, J=8.1 Hz), 7.98(d, 1H, J=15.3 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.78-7.85 (m, 2H), 7.77 (d,1H, J=15.3 Hz), 7.62 (d, 1H, J=5.1 Hz), 7.57 (s, 2H), 7.19 (dd, 1H,J=5.1, 3.6 Hz), 7.04 (d, 1H, J=7.5 Hz), 6.99 (s, 1H), 6.91 (d, 1H, J=8.4Hz), 3.90 (s, 3H), 2.33 (s, 3H). Anal. Calcd. C₂₆H₂₂N₂O₅S₂: C, 61.64; H,4.38; N, 5.53; S, 12.66. Found: C, 61.88; H, 4.47; N, 5.59; S, 12.62.

Example 123

5-Iodo-2,4-dimethoxy-benzaldehyde

To a solution of 2,4-dimethoxy-benzaldehyde (20.0 g, 120.4 mmol) inmethanol (550 mL) was added a solution of iodine monochloride (23.52 g,144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution wasallowed to stir at ambient temperature for 3 hours and then poured intoa solution of hydrochloric acid (0.5 M, 600 mL). The resultingprecipitate was collected by filtration, washed with water, and dried invacuo. The crude product was further recrystallized from a mixture oftetrahydrofuran and heptane (1:1, v/v) to give the tiltle compound as awhite solid (30.62 g, 87.5%), m.p. 170-172° C. ¹H NMR (CDCl₃) δ 10.19(s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H).

Example 124

5Benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde

Ex-123A: Potassium fluoride (0.42 g, 7.2 mmol),5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, 11.0 g, 3.42 mmol),2-benzo[b]thiophene boronic acid (0.67 g, 3.77 mmol), degasedtetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (19 mg,0.02 mmol), and tri-tert-butylphosphine (100 mg, 0.05 mmol) weresequentially charged into a flask equipped with a condenser and nitrogeninlet adapter. The reaction mixture was heated at 60° C. for one hourunder nitrogen. HPLC analysis indicated of 100% conversion of5-iodo-2,4-dimethoxy- benzaldehyde (Ex-123) to the title compoundprepared through another route (Ex-3A).

Using one or more of the preceding methods, additional substituted1-[2,2-bis(hydroxymethyl)-benzo[1,3]dioxol-5-yl]-3-[(heteroaryl orheterocyclic)phenyl]-2-propen-1-ones, 4-[3-{(heteroaryl orheterocyclic)phenyl}acryloyl]-benzoic acids,1-[(amino)phenyl]-3-[(heteroaryl orheterocyclic)phenyl]-2-propen-1-ones, 4-[3-{(heteroaryl orheterocyclic)phenyl}-3-oxo-propenyl]-benzoic acids,1-(1H-indol-5-yl)-3-{(heteroaryl or heterocyclic)phenyl}-propen-2-ones,1-[(heteroaryl or heterocyclic)phenyl]-3-phenyl-2-propen-1-ones, andsubstituted 3-[(heteroaryl orheterocyclic)phenyl]-1-phenyl-2-propen-1-ones can be prepared by oneskilled in the art using similar methods, as shown in Example Tables 1through 33. EXAMPLE TABLE 1 Substituted4-[3-{2-Isopropoxy-4-methoxy-(5-heteroaryl or 5-heterocyclic)phenyl}-acryloyl]-benzoic Acids.

Ex. No. R^(5β) 200A 200B

201A 201B

202A 202B

203A 203B

204A 204B

205A 205B

206A 206B

207A 207B

208A 208B

209A 209B

210A 210B

211A 211B

212A 212B

213A 213B

214A 214B

215A 215B

216A 216B

217A 217B

218A 218B

219A 219B

220A 220B

221A 221B

222A 222B

223A 223B

224A 224B

225A 225B

226A 226B

227A 227B

228A 228B

229A 229B

230A 230B

231A 231B

232A 232B

233A 233B

234A 234B

235A 235B

236A 236B

237A 237B

238A 238B

239A 239B

240A 240B

241A 241B

242A 242B

243A 243B

244A 244B

245A 245B

246A 246B

247A 247B

248A 248B

249A 249B

250A 250B

251A 251B

252A 252B

253A 253B

254A 254B

255A 255B

256A 256B

257A 257B

258A 258B

259A 259B

260A 260B

261A 261B

262A 262B

EXAMPLE TABLE 12Substituted4-[3-{2-Cyclopropylmethoxy-4-methoxy-(5-heteroaryl or 5-heterocyclic)phenyl}-acryloyl]-benzoic Acids.

Ex. No. R^(5β) 263A 263B

264A 264B

265A 265B

266A 266B

267A 267B

268A 268B

269A 269B

270A 270B

271A 271B

272A 272B

273A 273B

274A 274B

275A 275B

276A 276B

277A 277B

278A 278B

279A 279B

280A 280B

281A 281B

282A 282B

283A 283B

284A 284B

285A 285B

286A 286B

287A 287B

288A 288B

289A 289B

290A 290B

291A 291B

292A 292B

293A 293B

294A 294B

295A 295B

296A 296B

297A 297B

298A 298B

299A 299B

300A 300B

301A 301B

302A 302B

303A 303B

304A 304B

305A 305B

306A 306B

307A 307B

308A 308B

309A 309B

310A 310B

311A 311B

312A 312B

313A 313B

314A 314B

315A 315B

316A 316B

317A 317B

318A 318B

319A 319B

320A 320B

321A 321B

322A 322B

323A 323B

324A 324B

325A 325B

326A 326B

327A 327B

328A 328B

329A 329B

330A 330B

331A 331B

332A 332B

333A 333B

334A 334B

EXAMPLE TABLE 3 Substituted 4-[3-{2,4-dimethoxy-(6-Heteroaryl or6-heterocyclic)phenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 335A 335B

336A 336B

337A 337B

338A 338B

339A 339B

340A 340B

341A 341B

342A 342B

343A 343B

344A 344B

345A 345B

346A 346B

347A 347B

348A 348B

349A 349B

350A 350B

351A 351B

352A 352B

353A 353B

354A 354B

355A 355B

356A 356B

357A 357B

358A 358B

359A 359B

360A 360B

361A 361B

362A 362B

363A 363B

364A 364B

365A 365B

366A 366B

367A 367B

368A 368B

369A 369B

370A 370B

371A 371B

372A 372B

373A 373B

374A 374B

375A 375B

376A 376B

377A 377B

378A 378B

379A 379B

380A 380B

381A 381B

382A 382B

383A 383B

384A 384B

385A 385B

386A 386B

387A 387B

388A 388B

389A 389B

390A 390B

391A 391B

392A 392B

393A 393B

394A 394B

395A 395B

396A 396B

397A 397B

EXAMPLE TABLE 4 Substituted1-(2,2-Bis-hydroxymethyl-benzo[1,3]dioxol-5-yl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 398A 398B

399A 399B

400A 400B

401A 401B

402A 402B

403A 403B

404A 404B

405A 405B

406A 406B

407A 407B

408A 408B

409A 409B

410A 410B

411A 411B

412A 412B

413A 413B

414A 414B

415A 415B

416A 416B

417A 417B

418A 418B

419A 419B

420A 420B

421A 421B

422A 422B

423A 423B

424A 424B

425A 425B

426A 426B

427A 427B

428A 428B

429A 429B

430A 430B

431A 431B

432A 432B

433A 433B

434A 434B

435A 435B

436A 436B

437A 437B

438A 438B

439A 439B

440A 440B

441A 441B

442A 442B

443A 443B

444A 444B

445A 445B

446A 446B

447A 447B

448A 448B

449A 449B

450A 450B

451A 451B

452A 452B

453A 453B

454A 454B

455A 455B

456A 456B

457A 457B

458A 458B

459A 459B

460A 460B

461A 461B

462A 462B

463A 463B

464A 464B

465A 465B

466A 466B

467A 467B

468A 468B

469A 469B

EXAMPLE TABLE 5 Substituted1-(3-Aminophenyl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 470A 470B

471A 471B

472A 472B

473A 473B

474A 474B

475A 475B

476A 476B

477A 477B

478A 478B

479A 479B

480A 480B

481A 481B

482A 482B

483A 483B

484A 484B

485A 485B

486A 486B

487A 487B

488A 488B

489A 489B

490A 490B

491A 491B

492A 492B

493A 493B

494A 494B

495A 495B

496A 496B

497A 497B

498A 498B

499A 499B

500A 500B

501A 501B

502A 502B

503A 503B

504A 504B

505A 505B

506A 506B

507A 507B

508A 508B

509A 509B

510A 510B

511A 511B

512A 512B

513A 513B

514A 514B

515A 515B

516A 516B

517A 517B

518A 518B

519A 519B

520A 520B

521A 521B

522A 522B

523A 523B

524A 524B

525A 525B

526A 526B

527A 527B

528A 528B

529A 529B

530A 530B

531A 531B

532A 532B

EXAMPLE TABLE 6 Substituted1-(4-Aminophenyl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 533A 533B

534A 534B

535A 535B

536A 536B

537A 537B

538A 538B

539A 539B

540A 540B

541A 541B

542A 542B

543A 543B

544A 544B

545A 545B

546A 546B

547A 547B

548A 548B

549A 549B

550A 550B

551A 551B

552A 552B

553A 553B

554A 554B

555A 555B

556A 556B

557A 557B

558A 558B

559A 559B

560A 560B

561A 561B

562A 562B

563A 563B

564A 564B

565A 565B

566A 566B

567A 567B

568A 568B

569A 569B

570A 570B

571A 571B

572A 572B

573A 573B

574A 574B

575A 575B

576A 576B

577A 577B

578A 578B

579A 579B

580A 580B

581A 581B

582A 582B

583A 583B

584A 584B

585A 585B

586A 586B

587A 587B

588A 588B

589A 589B

590A 590B

591A 591B

592A 592B

593A 593B

594A 594B

595A 595B

596A 596B

597A 597B

598A 598B

599A 599B

600A 600B

601A 601B

602A 602B

603A 603B

604A 604B

EXAMPLE TABLE 7 Substituted1-{4-(Pyrrolidin-1-yl)phenyl}-3-[2,4-dimethoxy-(5-heteroaryl or5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 605A 605B

606A 606B

607A 607B

608A 608B

609A 609B

610A 610B

611A 611B

612A 612B

613A 613B

614A 614B

615A 615B

616A 616B

617A 617B

618A 618B

619A 619B

620A 620B

621A 621B

622A 622B

623A 623B

624A 624B

625A 625B

626A 626B

627A 627B

628A 628B

629A 629B

630A 630B

631A 631B

632A 632B

633A 633B

634A 634B

635A 635B

636A 636B

637A 637B

638A 638B

639A 639B

640A 640B

641A 641B

642A 642B

643A 643B

644A 644B

645A 645B

646A 646B

647A 647B

648A 648B

649A 649B

650A 650B

651A 651B

652A 652B

653A 653B

654A 654B

655A 655B

656A 656B

657A 657B

658A 658B

659A 659B

660A 660B

661A 661B

662A 662B

663A 663B

664A 664B

665A 665B

666A 666B

667A 667B

EXAMPLE TABLE 8 Substituted1-{4-(Methanesulfonylamino)phenyl}-3-[2,4-dimethoxy-(5- heteroaryl or5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 668A 668B

669A 669B

670A 670B

671A 671B

672A 672B

673A 673B

674A 674B

675A 675B

676A 676B

677A 677B

678A 678B

679A 679B

680A 680B

681A 681B

682A 682B

683A 683B

684A 684B

685A 685B

686A 686B

687A 687B

688A 688B

689A 689B

690A 690B

691A 691B

692A 692B

693A 693B

694A 694B

695A 695B

696A 696B

697A 697B

698A 698B

699A 699B

700A 700B

701A 701B

702A 702B

703A 703B

704A 704B

705A 705B

706A 706B

707A 707B

708A 708B

709A 709B

710A 710B

711A 711B

712A 712B

713A 713B

714A 714B

715A 715B

716A 716B

717A 717B

718A 718B

719A 719B

720A 720B

721A 721B

722A 722B

723A 723B

724A 724B

725A 725B

726A 726B

727A 727B

728A 728B

729A 729B

730A 730B

731A 731B

732A 732B

733A 733B

734A 734B

735A 735B

736A 736B

737A 737B

738A 738B

739A 739B

EXAMPLE TABLE 9 Substituted1-{4-(Methanesulfonylamino)phenyl}-3-[3,4-dimethoxy-(5- heteroaryl or5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 740A 740B

741A 741B

742A 742B

743A 743B

744A 744B

745A 745B

746A 746B

747A 747B

748A 748B

749A 749B

750A 750B

751A 751B

752A 752B

753A 753B

754A 754B

755A 755B

756A 756B

757A 757B

758A 758B

759A 759B

760A 760B

761A 761B

762A 762B

763A 763B

764A 764B

765A 765B

766A 766B

767A 767B

768A 768B

769A 769B

770A 770B

771A 771B

772A 772B

773A 773B

774A 774B

775A 775B

776A 776B

777A 777B

778A 778B

779A 779B

780A 780B

781A 781B

782A 782B

783A 783B

784A 784B

785A 785B

786A 786B

787A 787B

788A 788B

789A 789B

790A 790B

791A 791B

792A 792B

793A 793B

794A 794B

795A 795B

796A 796B

797A 797B

798A 798B

799A 799B

800A 800B

801A 801B

802A 802B

EXAMPLE TABLE 10 Substituted1-{4-(Amino)phenyl}-3-[3,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 803A 803B

804A 804B

805A 805B

806A 806B

807A 807B

808A 808B

809A 809B

810A 810B

811A 811B

812A 812B

813A 813B

814A 814B

815A 815B

816A 816B

817A 817B

818A 818B

819A 819B

820A 820B

821A 821B

822A 822B

823A 823B

824A 824B

825A 825B

826A 826B

827A 827B

828A 828B

829A 829B

830A 830B

831A 831B

832A 832B

833A 833B

834A 834B

835A 835B

836A 836B

837A 837B

838A 838B

839A 839B

840A 840B

841A 841B

842A 842B

843A 843B

844A 844B

845A 845B

846A 846B

847A 847B

848A 848B

849A 849B

850A 850B

851A 851B

852A 852B

853A 853B

854A 854B

855A 855B

856A 856B

857A 857B

858A 858B

859A 859B

860A 860B

861A 861B

862A 862B

863A 863B

864A 864B

865A 865B

866A 866B

867A 867B

868A 868B

869A 869B

870A 870B

871A 871B

872A 872B

873A 873B

874A 874B

EXAMPLE TABLE 11 Substituted1-{4-(Amino)phenyl}-3-[2,6-dimethoxy-(4-heteroaryl or 4-heterocylic)-phenyl]-2-propen-1-ones.

Ex. No. R^(4β) 875A 875B

876A 876B

877A 877B

878A 878B

879A 879B

880A 880B

881A 881B

882A 882B

883A 883B

884A 884B

885A 885B

886A 886B

887A 887B

888A 888B

889A 889B

890A 890B

891A 891B

892A 892B

893A 893B

894A 894B

895A 895B

896A 896B

897A 897B

898A 898B

899A 899B

900A 900B

901A 901B

902A 902B

903A 903B

904A 904B

905A 905B

906A 906B

907A 907B

908A 908B

909A 909B

910A 910B

911A 911B

912A 912B

913A 913B

914A 914B

915A 915B

916A 916B

917A 917B

918A 918B

919A 919B

920A 920B

921A 921B

922A 922B

923A 923B

924A 924B

925A 925B

926A 926B

927A 927B

928A 928B

929A 929B

930A 930B

931A 931B

932A 932B

933A 933B

934A 934B

935A 935B

936A 936B

937A 937B

EXAMPLE TABLE 12 Substituted1-{4-(Methanesulfonylamino)phenyl}-3-[2,6-dimethoxy-(4- heteroaryl or4-heterocylic)phenyl]-2-propen-1-ones.

Ex. No. R^(4β) 938A 938B

939A 939B

940A 940B

941A 941B

942A 942B

943A 943B

944A 944B

945A 945B

946A 946B

947A 947B

948A 948B

949A 949B

950A 950B

951A 951B

952A 952B

953A 953B

954A 954B

955A 955B

956A 956B

957A 957B

958A 958B

959A 959B

960A 960B

961A 961B

962A 962B

963A 963B

964A 964B

965A 965B

966A 966B

967A 967B

968A 968B

969A 969B

970A 970B

971A 971B

972A 972B

973A 973B

974A 974B

975A 975B

976A 976B

977A 977B

978A 978B

979A 979B

980A 980B

981A 981B

982A 982B

983A 983B

984A 984B

985A 985B

986A 986B

987A 987B

988A 988B

989A 989B

990A 990B

991A 991B

992A 992B

993A 993B

994A 994B

995A 995B

996A 996B

997A 997B

998A 998B

999A 999B

1000A 1000B

1001A 1001B

1002A 1002B

1003A 1003B

1004A 1004B

1005A 1005B

1006A 1006B

1007A 1007B

1008A 1008B

1009A 1009B

EXAMPLE TABLE 13 Substituted1-(1H-Indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl orheterocyclic)phenyl}-propen-2-ones.

Ex. No. R^(5β) 1010A 1010B

1011A 1011B

1012A 1012B

1013A 1013B

1014A 1014B

1015A 1015B

1016A 1016B

1017A 1017B

1018A 1018B

1019A 1019B

1020A 1020B

1021A 1021B

1022A 1022B

1023A 1023B

1024A 1024B

1025A 1025B

1026A 1026B

1027A 1027B

1028A 1028B

1029A 1029B

1030A 1030B

1031A 1031B

1032A 1032B

1033A 1033B

1034A 1034B

1035A 1035B

1036A 1036B

1037A 1037B

1038A 1038B

1039A 1039B

1040A 1040B

1041A 1041B

1042A 1042B

1043A 1043B

1044A 1044B

1045A 1045B

1046A 1046B

1047A 1047B

1048A 1048B

1049A 1049B

1050A 1050B

1051A 1051B

1052A 1052B

1053A 1053B

1054A 1054B

1055A 1055B

1056A 1056B

1057A 1057B

1058A 1058B

1059A 1059B

1060A 1060B

1061A 1061B

1062A 1062B

1063A 1063B

1064A 1064B

1065A 1065B

1066A 1066B

1067A 1067B

1068A 1068B

1069A 1069B

1070A 1070B

1071A 1071B

1072A 1072B

EXAMPLE TABLE 14 Substituted1-(1H-Indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl orheterocyclic)phenyl}-propen-2-ones.

Ex. No. R^(5β) 1073A 1073B

1074A 1074B

1075A 1075B

1076A 1076B

1077A 1077B

1078A 1078B

1079A 1079B

1080A 1080B

1081A 1081B

1082A 1082B

1083A 1083B

1084A 1084B

1085A 1085B

1086A 1086B

1087A 1087B

1088A 1088B

1089A 1089B

1090A 1090B

1091A 1091B

1092A 1092B

1093A 1093B

1094A 1094B

1095A 1095B

1096A 1096B

1097A 1097B

1098A 1098B

1099A 1099B

1100A 1100B

1101A 1101B

1102A 1102B

1103A 1103B

1104A 1104B

1105A 1105B

1106A 1106B

1107A 1107B

1108A 1108B

1109A 1109B

1110A 1110B

1111A 1111B

1112A 1112B

1113A 1113B

1114A 1114B

1115A 1115B

1116A 1116B

1117A 1117B

1118A 1118B

1119A 1119B

1120A 1120B

1121A 1121B

1122A 1122B

1123A 1123B

1124A 1124B

1125A 1125B

1126A 1126B

1127A 1127B

1128A 1128B

1129A 1129B

1130A 1130B

1131A 1131B

1132A 1132B

1133A 1133B

1134A 1134B

1135A 1135B

1136A 1136B

1137A 1137B

1138A 1138B

1139A 1139B

1140A 1140B

1141A 1141B

1142A 1142B

1143A 1143B

1144A 1144B

EXAMPLE TABLE 15 Substituted1-(1H-1-Methyl-indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl orheterocyclic)phenyl}-propen-2-ones.

Ex. No. R^(5β) 1145A 1145B

1146A 1146B

1147A 1147B

1148A 1148B

1149A 1149B

1150A 1150B

1151A 1151B

1152A 1152B

1153A 1153B

1154A 1154B

1155A 1155B

1156A 1156B

1157A 1157B

1158A 1158B

1159A 1159B

1160A 1160B

1161A 1161B

1162A 1162B

1163A 1163B

1164A 1164B

1165A 1165B

1166A 1166B

1167A 1167B

1168A 1168B

1169A 1169B

1170A 1170B

1171A 1171B

1172A 1172B

1173A 1173B

1174A 1174B

1175A 1175B

1176A 1176B

1177A 1177B

1178A 1178B

1179A 1179B

1180A 1180B

1181A 1181B

1182A 1182B

1183A 1183B

1184A 1184B

1185A 1185B

1186A 1186B

1187A 1187B

1188A 1188B

1189A 1189B

1190A 1190B

1191A 1191B

1192A 1192B

1193A 1193B

1194A 1194B

1195A 1195B

1196A 1196B

1197A 1197B

1198A 1198B

1199A 1199B

1200A 1200B

1201A 1201B

1202A 1202B

1203A 1203B

1204A 1204B

1205A 1205B

1206A 1206B

1207A 1207B

EXAMPLE TABLE 17 Substituted1-(1H-1-Methyl-indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl orheterocyclic)phenyl}-propen-2-ones.

Ex. No. R^(5β) 1208A 1208B

1209A 1209B

1210A 1210B

1211A 1211B

1212A 1212B

1213A 1213B

1214A 1214B

1215A 1215B

1216A 1216B

1217A 1217B

1218A 1218B

1219A 1219B

1220A 1220B

1221A 1221B

1222A 1222B

1223A 1223B

1224A 1224B

1225A 1225B

1226A 1226B

1227A 1227B

1228A 1228B

1229A 1229B

1230A 1230B

1231A 1231B

1232A 1232B

1233A 1233B

1234A 1234B

1235A 1235B

1236A 1236B

1237A 1237B

1238A 1238B

1239A 1239B

1240A 1240B

1241A 1241B

1242A 1242B

1243A 1243B

1244A 1244B

1245A 1245B

1246A 1246B

1247A 1247B

1248A 1248B

1249A 1249B

1250A 1250B

1251A 1251B

1252A 1252B

1253A 1253B

1254A 1254B

1255A 1255B

1256A 1256B

1257A 1257B

1258A 1258B

1259A 1259B

1260A 1260B

1261A 1261B

1262A 1262B

1263A 1263B

1264A 1264B

1265A 1265B

1266A 1266B

1267A 1267B

1268A 1268B

1269A 1269B

1270A 1270B

1271A 1271B

1272A 1272B

1273A 1273B

1274A 1274B

1275A 1275B

1276A 1276B

1277A 1277B

1278A 1278B

1279A 1279B

EXAMPLE TABLE 17 Substituted 4-[3-{2-(Pyrrolidin-1-yl)-(4-heteroaryl or4-heterocyclic)- phenyl}-acryloyl]-benzoic Acids.

Ex. No. R^(4β) 1280A 1280B

1281A 1281B

1282A 1282B

1283A 1283B

1284A 1284B

1285A 1285B

1286A 1286B

1287A 1287B

1288A 1288B

1289A 1289B

1290A 1290B

1291A 1291B

1292A 1292B

1293A 1293B

1294A 1294B

1295A 1295B

1296A 1296B

1297A 1297B

1298A 1298B

1299A 1299B

1300A 1300B

1301A 1301B

1302A 1302B

1303A 1303B

1304A 1304B

1305A 1305B

1306A 1306B

1307A 1307B

1308A 1308B

1309A 1309B

1310A 1310B

1311A 1311B

1312A 1312B

1313A 1313B

1314A 1314B

1315A 1315B

1316A 1316B

1317A 1317B

1318A 1318B

1319A 1319B

1320A 1320B

1321A 1321B

1322A 1322B

1323A 1323B

1324A 1324B

1325A 1325B

1326A 1326B

1327A 1327B

1328A 1328B

1329A 1329B

1330A 1330B

1331A 1331B

1332A 1332B

1333A 1333B

1334A 1334B

1335A 1335B

1336A 1336B

1337A 1337B

1338A 1338B

1339A 1339B

1340A 1340B

1341A 1341B

1342A 1342B

1343A 1343B

1344A 1344B

1345A 1345B

1346A 1346B

1347A 1347B

1348A 1348B

1349A 1349B

1350A 1350B

1351A 1351B

EXAMPLE TABLE 18 Substituted 4-[3-{(5-Heteroaryl or5-heterocyclic)-2,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1352A 1352B

1353A 1353B

1354A 1354B

1355A 1355B

1356A 1356B

1357A 1357B

1358A 1358B

1359A 1359B

1360A 1360B

1361A 1361B

1362A 1362B

1363A 1363B

1364A 1364B

1365A 1365B

1366A 1366B

1367A 1367B

1368A 1368B

1369A 1369B

1370A 1370B

1371A 1371B

1372A 1372B

1373A 1373B

1374A 1374B

1375A 1375B

1376A 1376B

1377A 1377B

1378A 1378B

1379A 1379B

1380A 1380B

1381A 1381B

1382A 1382B

1383A 1383B

1384A 1384B

1385A 1385B

1386A 1386B

1387A 1387B

1388A 1388B

1389A 1389B

1390A 1390B

1391A 1391B

1392A 1392B

1393A 1393B

1394A 1394B

1395A 1395B

1396A 1396B

1397A 1397B

1398A 1398B

1399A 1399B

1360A 1360B

1401A 1401B

1402A 1402B

1403A 1403B

1404A 1404B

1405A 1405B

1406A 1406B

1407A 1407B

1408A 1408B

1409A 1409B

1410A 1410B

1411A 1411B

1412A 1412B

1413A 1413B

1414A 1414B

EXAMPLE TABLE 19 Substituted 3-[3-{(5-Heteroaryl or5-heterocyclic)-2,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1415A 1415B

1416A 1416B

1417A 1417B

1418A 1418B

1419A 1419B

1420A 1420B

1421A 1421B

1422A 1422B

1423A 1423B

1424A 1424B

1425A 1425B

1426A 1426B

1427A 1427B

1428A 1428B

1429A 1429B

1430A 1430B

1431A 1431B

1432A 1432B

1433A 1433B

1434A 1434B

1435A 1435B

1436A 1436B

1437A 1437B

1438A 1438B

1439A 1439B

1440A 1440B

1441A 1441B

1442A 1442B

1443A 1443B

1444A 1444B

1445A 1445B

1446A 1446B

1447A 1447B

1448A 1448B

1449A 1449B

1450A 1450B

1451A 1451B

1452A 1452B

1453A 1453B

1454A 1454B

1455A 1455B

1456A 1456B

1457A 1457B

1458A 1458B

1459A 1459B

1460A 1460B

1461A 1461B

1462A 1462B

1463A 1463B

1464A 1464B

1465A 1465B

1466A 1466B

1467A 1467B

1468A 1468B

1469A 1469B

1470A 1470B

1471A 1471B

1473A 1473B

1474A 1474B

1475A 1475B

1476A 1476B

1477A 1477B

1478A 1478B

1479A 1479B

1480A 1480B

1481A 1481B

1482A 1482B

1483A 1483B

1484A 1484B

1485A 1485B

1486A 1486B

1487A 1487B

EXAMPLE TABLE 20 Substituted 2-[3-{(5-Heteroaryl or5-heterocyclic)-2,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1488A 1488B

1489A 1489B

1490A 1490B

1491A 1491B

1492A 1492B

1493A 1493B

1494A 1494B

1495A 1495B

1496A 1496B

1497A 1497B

1498A 1498B

1499A 1499B

1500A 1500B

1501A 1501B

1502A 1502B

1503A 1503B

1504A 1504B

1505A 1505B

1506A 1506B

1507A 1507B

1508A 1508B

1509A 1509B

1510A 1510B

1511A 1511B

1512A 1512B

1513A 1513B

1514A 1514B

1515A 1515B

1516A 1516B

1517A 1517B

1518A 1518B

1519A 1519B

1520A 1520B

1521A 1521B

1522A 1522B

1523A 1523B

1524A 1524B

1525A 1525B

1526A 1526B

1527A 1527B

1528A 1528B

1529A 1529B

1530A 1530B

1531A 1531B

1532A 1532B

1533A 1533B

1534A 1534B

1535A 1535B

1536A 1536B

1537A 1537B

1538A 1538B

1539A 1539B

1540A 1540B

1541A 1541B

1542A 1542B

1543A 1543B

1544A 1544B

1545A 1545B

1546A 1546B

1547A 1547B

1548A 1548B

1549A 1549B

1550A 1550B

EXAMPLE TABLE 21 Substituted 2-[3-{(5-Heteroaryl or5-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]-5-methanesulfonylamino-benzoic Acids.

Ex. No. R^(5β) 1551A 1551B

1552A 1552B

1553A 1553B

1554A 1554B

1555A 1555B

1556A 1556B

1557A 1557B

1558A 1558B

1559A 1559B

1560A 1560B

1561A 1561B

1562A 1562B

1563A 1563B

1564A 1564B

1565A 1565B

1566A 1566B

1567A 1567B

1568A 1568B

1569A 1569B

1570A 1570B

1571A 1571B

1572A 1572B

1573A 1573B

1574A 1574B

1575A 1575B

1576A 1576B

1577A 1577B

1578A 1578B

1579A 1579B

1580A 1580B

1581A 1581B

1582A 1582B

1583A 1583B

1584A 1584B

1585A 1585B

1586A 1586B

1587A 1587B

1588A 1588B

1589A 1589B

1590A 1590B

1591A 1591B

1592A 1592B

1593A 1593B

1594A 1594B

1595A 1595B

1596A 1596B

1597A 1597B

1598A 1598B

1599A 1599B

1600A 1600B

1601A 1601B

1602A 1602B

1603A 1603B

1604A 1604B

1605A 1605B

1606A 1606B

1607A 1607B

1608A 1608B

1609A 1609B

1610A 1610B

1611A 1611B

1612A 1612B

1613A 1613B

1614A 1614B

1615A 1615B

1616A 1616B

1617A 1617B

1618A 1618B

1619A 1619B

1620A 1620B

1621A 1621B

1622A 1622B

EXAMPLE TABLE 22 Substituted 5-Amino-2-[3-{(5-heteroaryl or5-heterocyclic)-2,4- dimethoxy-phenyl}-acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1623A 1623B

1624A 1624B

1625A 1625B

1626A 1626B

1627A 1627B

1628A 1628B

1629A 1629B

1630A 1630B

1631A 1631B

1632A 1632B

1633A 1633B

1634A 1634B

1635A 1635B

1636A 1636B

1637A 1637B

1638A 1638B

1639A 1639B

1640A 1640B

1641A 1641B

1642A 1642B

1643A 1643B

1644A 1644B

1645A 1645B

1646A 1646B

1647A 1647B

1648A 1648B

1649A 1649B

1650A 1650B

1651A 1651B

1652A 1652B

1653A 1653B

1654A 1654B

1655A 1655B

1656A 1656B

1657A 1657B

1658A 1658B

1659A 1659B

1660A 1660B

1661A 1661B

1662A 1662B

1663A 1663B

1664A 1664B

1665A 1665B

1666A 1666B

1667A 1667B

1668A 1668B

1669A 1669B

1670A 1670B

1671A 1671B

1672A 1672B

1673A 1673B

1674A 1674B

1675A 1675B

1676A 1676B

1677A 1677B

1678A 1678B

1679A 1679B

1680A 1680B

1681A 1681B

1682A 1682B

1683A 1683B

1684A 1684B

1685A 1685B

EXAMPLE TABLE 23 Substituted 4-[3-{(5-Heteroaryl or5-heterocyclic)-3,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1686A 1686B

1687A 1687B

1688A 1688B

1689A 1689B

1690A 1690B

1691A 1691B

1692A 1692B

1693A 1693B

1694A 1694B

1695A 1695B

1696A 1696B

1697A 1697B

1698A 1698B

1699A 1699B

1700A 1700B

1701A 1701B

1702A 1702B

1703A 1703B

1704A 1704B

1705A 1705B

1706A 1706B

1707A 1707B

1708A 1708B

1709A 1709B

1710A 1710B

1711A 1711B

1712A 1712B

1713A 1713B

1714A 1714B

1715A 1715B

1716A 1716B

1717A 1717B

1718A 1718B

1719A 1719B

1720A 1720B

1721A 1721B

1722A 1722B

1723A 1723B

1724A 1724B

1725A 1725B

1726A 1726B

1727A 1727B

1728A 1728B

1729A 1729B

1730A 1730B

1731A 1731B

1732A 1732B

1733A 1733B

1734A 1734B

1735A 1735B

1736A 1736B

1737A 1737B

1738A 1738B

1739A 1739B

1740A 1740B

1741A 1741B

1742A 1742B

1743A 1743B

1744A 1744B

1745A 1745B

1746A 1746B

1747A 1747B

1748A 1748B

1749A 1749B

1750A 1750B

1751A 1751B

1752A 1752B

1753A 1753B

1754A 1754B

1755A 1755B

1756A 1756B

1757A 1757B

EXAMPLE TABLE 24 Substituted 3-[3-{(5-Heteroaryl or5-heterocyclic)-3,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1758A 1758B

1759A 1759B

1760A 1760B

1761A 1761B

1762A 1762B

1763A 1763B

1764A 1764B

1765A 1765B

1766A 1766B

1767A 1767B

1768A 1768B

1769A 1769B

1770A 1770B

1771A 1771B

1772A 1772B

1773A 1773B

1774A 1774B

1775A 1775B

1776A 1776B

1777A 1777B

1778A 1778B

1779A 1779B

1780A 1780B

1781A 1781B

1782A 1782B

1783A 1783B

1784A 1784B

1785A 1785B

1786A 1786B

1787A 1787B

1788A 1788B

1789A 1789B

1790A 1790B

1791A 1791B

1792A 1792B

1793A 1793B

1794A 1794B

1795A 1795B

1796A 1796B

1797A 1797B

1798A 1798B

1799A 1799B

1800A 1800B

1801A 1801B

1802A 1802B

1803A 1803B

1804A 1804B

1805A 1805B

1806A 1806B

1807A 1807B

1808A 1808B

1809A 1809B

1810A 1810B

1811A 1811B

1812A 1812B

1813A 1813B

1814A 1814B

1815A 1815B

1816A 1816B

1817A 1817B

1818A 1818B

1819A 1819B

1820A 1820B

EXAMPLE TABLE 25 Substituted 2-[3-{(5-Heteroaryl or5-heterocyclic)-3,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1821A 1821B

1822A 1822B

1823A 1823B

1824A 1824B

1825A 1825B

1826A 1826B

1827A 1827B

1828A 1828B

1829A 1829B

1830A 1830B

1831A 1831B

1832A 1832B

1833A 1833B

1834A 1834B

1835A 1835B

1836A 1836B

1837A 1837B

1838A 1838B

1839A 1839B

1840A 1840B

1841A 1841B

1842A 1842B

1843A 1843B

1844A 1844B

1845A 1845B

1846A 1846B

1847A 1847B

1848A 1848B

1849A 1849B

1850A 1850B

1851A 1851B

1852A 1852B

1853A 1853B

1854A 1854B

1855A 1855B

1856A 1856B

1857A 1857B

1858A 1858B

1859A 1859B

1860A 1860B

1861A 1861B

1862A 1862B

1863A 1863B

1864A 1864B

1865A 1865B

1866A 1866B

1867A 1867B

1868A 1868B

1869A 1869B

1870A 1870B

1871A 1871B

1872A 1872B

1873A 1873B

1874A 1874B

1875A 1875B

1876A 1876B

1877A 1877B

1878A 1878B

1879A 1879B

1880A 1880B

1881A 1881B

1882A 1882B

1883A 1883B

1884A 1884B

1885A 1885B

1886A 1886B

1887A 1887B

1888A 1888B

1889A 1889B

1890A 1890B

1891A 1891B

1892A 1892B

EXAMPLE TABLE 26 Substituted 4-[3-{(5-Heteroaryl or5-heterocyclic)-4-fluorophenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1893A 1893B

1894A 1894B

1895A 1895B

1896A 1896B

1897A 1897B

1898A 1898B

1899A 1899B

1900A 1900B

1901A 1901B

1902A 1902B

1903A 1903B

1904A 1904B

1905A 1905B

1906A 1906B

1907A 1907B

1908A 1908B

1909A 1909B

1910A 1910B

1911A 1911B

1912A 1912B

1913A 1913B

1914A 1914B

1915A 1915B

1916A 1916B

1917A 1917B

1918A 1918B

1919A 1919B

1920A 1920B

1921A 1921B

1922A 1922B

1923A 1923B

1924A 1924B

1925A 1925B

1926A 1926B

1927A 1927B

1928A 1928B

1929A 1929B

1930A 1930B

1931A 1931B

1932A 1932B

1933A 1933B

1934A 1934B

1935A 1935B

1936A 1936B

1937A 1937B

1938A 1938B

1939A 1939B

1940A 1940B

1941A 1941B

1942A 1942B

1943A 1943B

1944A 1944B

1945A 1945B

1946A 1946B

1947A 1947B

1948A 1948B

1949A 1949B

1950A 1950B

1951A 1951B

1952A 1952B

1953A 1953B

1954A 1954B

1955A 1955B

EXAMPLE TABLE 27 Substituted 4-[3-{(3-Heteroaryl or3-heterocyclic)-4-(pyrrolidin-1-yl)- phenyl}acryloyl]-benzoic Acids.

Ex. No. R^(5β) 1956A 1956B

1957A 1957B

1958A 1958B

1959A 1959B

1960A 1960B

1961A 1961B

1962A 1962B

1963A 1963B

1964A 1964B

1965A 1965B

1966A 1966B

1967A 1967B

1968A 1968B

1969A 1969B

1970A 1970B

1971A 1971B

1972A 1972B

1973A 1973B

1974A 1974B

1975A 1975B

1976A 1976B

1977A 1977B

1978A 1978B

1979A 1979B

1980A 1980B

1981A 1981B

1982A 1982B

1983A 1983B

1984A 1984B

1985A 1985B

1986A 1986B

1987A 1987B

1988A 1988B

1989A 1989B

1990A 1990B

1991A 1991B

1992A 1992B

1993A 1993B

1994A 1994B

1995A 1995B

1996A 1996B

1997A 1997B

1998A 1998B

1999A 1999B

2000A 2000B

2001A 2001B

2002A 2002B

2003A 2003B

2004A 2004B

2005A 2005B

2006A 2006B

2007A 2007B

2008A 2008B

2009A 2009B

2010A 2010B

2011A 2011B

2012A 2012B

2013A 2013B

2014A 2014B

2015A 2015B

2016A 2016B

2017A 2017B

2018A 2018B

2019A 2019B

2020A 2020B

2021A 2021B

2022A 2022B

2023A 2023B

2024A 2024B

2025A 2025B

2026A 2026B

2027A 2027B

EXAMPLE TABLE 28 Substituted 4-[3-{(5-Heteroaryl or5-heterocyclic)-2,4-dimethoxyphenyl}- acryloyl]benzonitriles.

Ex. No. R^(5β) 2028A 2028B

2029A 2029B

2030A 2030B

2031A 2031B

2032A 2032B

2033A 2033B

2034A 2034B

2035A 2035B

2036A 2036B

2037A 2037B

2038A 2038B

2039A 2039B

2040A 2040B

2041A 2041B

2042A 2042B

2043A 2043B

2044A 2044B

2045A 2045B

2046A 2046B

2047A 2047B

2048A 2048B

2049A 2049B

2050A 2050B

2051A 2051B

2052A 2052B

2053A 2053B

2054A 2054B

2055A 2055B

2056A 2056B

2057A 2057B

2058A 2058B

2059A 2059B

2060A 2060B

2061A 2061B

2062A 2062B

2063A 2063B

2064A 2064B

2065A 2065B

2066A 2066B

2067A 2067B

2068A 2068B

2069A 2069B

2070A 2070B

2071A 2071B

2072A 2072B

2073A 2073B

2074A 2074B

2075A 2075B

2076A 2076B

2077A 2077B

2078A 2078B

2079A 2079B

2080A 2080B

2081A 2081B

2082A 2082B

2083A 2083B

2084A 2084B

2085A 2085B

2086A 2086B

2087A 2087B

2088A 2088B

2089A 2089B

2090A 2090B

EXAMPLE TABLE 29 Substituted 3-[2,4-Dimethoxy-(5-heteroaryl or5-heterocyclic)phenyl]- 1-[4-(2H-tetrazol-5-yl)phenyl]-2-propen-1-ones.

Ex. No. R^(5β) 2091A 2091B

2092A 2092B

2093A 2093B

2094A 2094B

2095A 2095B

2096A 2096B

2097A 2097B

2098A 2098B

2099A 2099B

2100A 2100B

2101A 2101B

2102A 2102B

2103A 2103B

2104A 2104B

2105A 2105B

2106A 2106B

2107A 2107B

2108A 2108B

2109A 2109B

2110A 2110B

2111A 2111B

2112A 2112B

2113A 2113B

2114A 2114B

2115A 2115B

2116A 2116B

2117A 2117B

2118A 2118B

2119A 2119B

2120A 2120B

2121A 2121B

2122A 2122B

2123A 2123B

2124A 2124B

2125A 2125B

2126A 2126B

2127A 2127B

2128A 2128B

2129A 2129B

2130A 2130B

2131A 2131B

2132A 2132B

2133A 2133B

2134A 2134B

2135A 2135B

2136A 2136B

2137A 2137B

2138A 2138B

2139A 2139B

2140A 2140B

2141A 2141B

2142A 2142B

2143A 2143B

2144A 2144B

2145A 2145B

2146A 2146B

2147A 2147B

2148A 2148B

2149A 2149B

2150A 2150B

2151A 2151B

2152A 2152B

2153A 2153B

2154A 2154B

2155A 2155B

2156A 2156B

2157A 2157B

2158A 2158B

2159A 2159B

2160A 2160B

2161A 2161B

2162A 2162B

EXAMPLE TABLE 30 Substituted 4-[3-{(4-Heteroaryl or4-heterocyclic)phenyl}-acryloyl]- benzoic Acids.

Ex. No. R^(4β) 2163A 2163B

2164A 2164B

2165A 2165B

2166A 2166B

2167A 2167B

2168A 2168B

2169A 2169B

2170A 2170B

2171A 2171B

2172A 2172B

2173A 2173B

2174A 2174B

2175A 2175B

2176A 2176B

2177A 2177B

2178A 2178B

2179A 2179B

2180A 2180B

2181A 2181B

2182A 2182B

2183A 2183B

2184A 2184B

2185A 2185B

2186A 2186B

2187A 2187B

2188A 2188B

2189A 2189B

2190A 2190B

2191A 2191B

2192A 2192B

2193A 2193B

2194A 2194B

2195A 2195B

2196A 2196B

2197A 2197B

2198A 2198B

2199A 2199B

2200A 2200B

2201A 2201B

2202A 2202B

2203A 2203B

2204A 2204B

2205A 2205B

2206A 2206B

2207A 2207B

2208A 2208B

2209A 2209B

2210A 2210B

2211A 2211B

2212A 2212B

2213A 2213B

2214A 2214B

2215A 2215B

2216A 2216B

2217A 2217B

2218A 2218B

2219A 2219B

2220A 2220B

2221A 2221B

2222A 2222B

2223A 2223B

2224A 2224B

2225A 2225B

EXAMPLE TABLE 31 Substituted 4-[3-{(4-Heteroaryl or4-heterocyclic)phenyl}-3-oxo- propenyl]-benzoic Acids.

Ex. No. R^(4α) 2226A 2226B

2227A 2227B

2228A 2228B

2229A 2229B

2230A 2230B

2231A 2231B

2232A 2232B

2233A 2233B

2234A 2234B

2235A 2235B

2236A 2236B

2237A 2237B

2238A 2238B

2239A 2239B

2240A 2240B

2241A 2241B

2242A 2242B

2243A 2243B

2244A 2244B

2245A 2245B

2246A 2246B

2247A 2247B

2248A 2248B

2249A 2249B

2250A 2250B

2251A 2251B

2252A 2252B

2253A 2253B

2254A 2254B

2255A 2255B

2256A 2256B

2257A 2257B

2258A 2258B

2259A 2259B

2260A 2260B

2261A 2261B

2262A 2262B

2263A 2263B

2264A 2264B

2265A 2265B

2266A 2266B

2267A 2267B

2268A 2268B

2269A 2269B

2270A 2270B

2271A 2271B

2272A 2272B

2273A 2273B

2274A 2274B

2275A 2275B

2276A 2276B

2277A 2277B

2278A 2278B

2279A 2279B

2280A 2280B

2281A 2281B

2282A 2282B

2283A 2283B

2284A 2284B

2285A 2285B

2286A 2286B

2287A 2287B

2288A 2288B

2289A 2289B

2290A 2290B

2291A 2291B

2292A 2292B

2293A 2293B

2294A 2294B

2295A 2295B

2296A 2296B

2297A 2297B

EXAMPLE TABLE 32 Substituted 4-[3-{(4-Heteroaryl or4-heterocyclic)-2,6-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(4β) 2298A 2298B

2299A 2299B

2300A 2300B

2301A 2301B

2302A 2302B

2303A 2303B

2304A 2304B

2305A 2305B

2306A 2306B

2307A 2307B

2308A 2308B

2309A 2309B

2310A 2310B

2311A 2311B

2312A 2312B

2313A 2313B

2314A 2314B

2315A 2315B

2316A 2316B

2317A 2317B

2318A 2318B

2319A 2319B

2320A 2320B

2321A 2321B

2322A 2322B

2323A 2323B

2324A 2324B

2325A 2325B

2326A 2326B

2327A 2327B

2328A 2328B

2329A 2329B

2330A 2330B

2331A 2331B

2332A 2332B

2333A 2333B

2334A 2334B

2335A 2335B

2336A 2336B

2337A 2337B

2338A 2338B

2339A 2339B

2340A 2340B

2341A 2341B

2342A 2342B

2343A 2343B

2344A 2344B

2345A 2345B

2346A 2346B

2347A 2347B

2348A 2348B

2349A 2349B

2350A 2350B

2351A 2351B

2352A 2352B

2353A 2353B

2354A 2354B

2355A 2355B

2356A 2356B

2357A 2357B

2358A 2358B

2359A 2359B

2360A 2360B

EXAMPLE TABLE 33 Substituted 4-[3-{(5-Heteroaryl or5-heterocyclic)-2,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R^(5β) 2361A 2361B

2362A 2362B

2363A 2363B

2364A 2364B

2365A 2365B

2366A 2366B

2367A 2367B

2368A 2368B

2369A 2369B

Stereoisomerism and Polymorphism

It is appreciated that compounds of the present invention having achiral center may exist in and be isolated in optically active andracemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, diastereomeric, polymorphic, or stereoisomeric form,or mixtures thereof, of a compound of the invention, which possess theuseful properties described herein, it being well known in the art howto prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

Examples of methods to obtain optically active materials are known inthe art, and include at least the following.

-   -   i) physical separation of crystals—a technique whereby        macroscopic crystals of the individual enantiomers are manually        separated. This technique can be used if crystals of the        separate enantiomers exist, i.e., the material is a        conglomerate, and the crystals are visually distinct;    -   ii) simultaneous crystallization—a technique whereby the        individual enantiomers are separately crystallized from a        solution of the racemate, possible only if the latter is a        conglomerate in the solid state;    -   iii) enzymatic resolutions—a technique whereby partial or        complete separation of a racemate by virtue of differing rates        of reaction for the enantiomers with an enzyme;    -   iv) enzymatic asymmetric synthesis—a synthetic technique whereby        at least one step of the synthesis uses an enzymatic reaction to        obtain an enantiomerically pure or enriched synthetic precursor        of the desired enantiomer;    -   v) chemical asymmetric synthesis—a synthetic technique whereby        the desired enantiomer is synthesized from an achiral precursor        under conditions that produce asymmetry (i.e., chirality) in the        product, which may be achieved using chiral catalysts or chiral        auxiliaries;    -   vi) diastereomer separations—a technique whereby a racemic        compound is reacted with an enantiomerically pure reagent (the        chiral auxiliary) that converts the individual enantiomers to        diastereomers. The resulting diastereomers are then separated by        chromatography or crystallization by virtue of their now more        distinct structural differences and the chiral auxiliary later        removed to obtain the desired enantiomer;    -   vii) first- and second-order asymmetric transformations—a        technique whereby diastereomers from the racemate equilibrate to        yield a preponderance in solution of the diastereomer from the        desired enantiomer or where preferential crystallization of the        diastereomer from the desired enantiomer perturbs the        equilibrium such that eventually in principle all the material        is converted to the crystalline diastereomer from the desired        enantiomer. The desired enantiomer is then released from the        diastereomer;    -   viii) kinetic resolutions—this technique refers to the        achievement of partial or complete resolution of a racemate (or        of a further resolution of a partially resolved compound) by        virtue of unequal reaction rates of the enantiomers with a        chiral, non-racemic reagent or catalyst under kinetic        conditions;    -   ix) enantiospecific synthesis from non-racemic precursors—a        synthetic technique whereby the desired enantiomer is obtained        from non-chiral starting materials and where the stereochemical        integrity is not or is only minimally compromised over the        course of the synthesis;    -   x) chiral liquid chromatography—a technique whereby the        enantiomers of a racemate are separated in a liquid mobile phase        by virtue of their differing interactions with a stationary        phase. The stationary phase can be made of chiral material or        the mobile phase can contain an additional chiral material to        provoke the differing interactions;    -   xi) chiral gas chromatopraphy—a technique whereby the racemate        is volatilized and enantiomers are separated by virtue of their        differing interactions in the gaseous mobile phase with a column        containing a fixed non-racemic chiral adsorbent phase;    -   xii) extraction with chiral solvents—a technique whereby the        enantiomers are separated by virtue of preferential dissolution        of one enantiomer into a particular chiral solvent;    -   xiii) transport across chiral membranes—a technique whereby a        racemate is placed in contact with a thin membrane barrier. The        barrier typically separates two miscible fluids, one containing        the racemate, and a driving force such as concentration or        pressure differential causes preferential transport across the        membrane barrier. Separation occurs as a result of the        non-racemic chiral nature of the membrane which allows only one        enantiomer of the racemate to pass through.        Pharmaceutically Acceptable Salt Formulations

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. The term“pharmaceutically acceptable salts” or “complexes” refers to salts orcomplexes that retain the desired biological activity of the compoundsof the present invention and exhibit minimal undesired toxicologicaleffects.

Examples of pharmaceutically acceptable salts are organic acid additionsalts formed with acids, which form a physiological acceptable anion,for example, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorbate, α-ketoglutarate andα-glycerophosphate. Suitable inorganic salts may also be formed,including, sulfate, nitrate, bicarbonate and carbonate salts.Alternatively, the pharmaceutically acceptable salts may be made withsufficiently basic compounds such as an amine with a suitable acidaffording a physiologically acceptable anion. Alkali metal (for example,sodium, potassium or lithium) or alkaline earth metal (for examplecalcium) salts of carboxylic acids can also be made.

Nonlimiting examples of such salts are (a) acid addition salts formedwith inorganic acids (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like), and saltsformed with organic acids such as acetic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) baseaddition salts formed with metal cations such as zinc, calcium, bismuth,barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium,potassium, and the like, or with a cation formed from ammonia,N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, orethylenediamine; or (c) combinations of (a) and (b); e.g., a zinctannate salt or the like. Also included in this definition arepharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR⁺A⁻, wherein R is as defined above and A is a counterion,including chloride, bromide, iodide, —O-alkyl, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, citrate, tartrate,ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, anddiphenylacetate).

Particular FDA-approved salts can be conveniently divided between anionsand cations (Approved Drug Products with Therapeutic EquivalenceEvaluations (1994) U.S. Department of Health and Human Services, PublicHealth Service, FDA, Center for Drug Evaluation and Research, Rockville,Md.; L. D. Bighley, S. M. Berge ad D. C. Monkhouse, Salt Forms of Drugsand Absorption, Encyclopedia of Pharmaceutical Technology, Vol. 13, J.Swarbridk and J. Boylan, eds., Marcel Dekker, NY (1996)). Among theapproved anions include aceglumate, acephyllinate, acetamidobenzoate,acetate, acetylasparaginate, acetylaspartate, adipate, aminosalicylate,anhydromethylenecitrate, ascorbate, aspartate, benzoate, besylate,bicarbonate, bisulfate, bitartrate, borate, bromide, camphorate,camsylate, carbonate, chloride, chlorophenoxyacetate, citrate,closylate, cromesilate, cyclamate, dehydrocholate, dihydrochloride,dimalonate, edentate, edisylate, estolate, esylate, ethylbromide,ethylsulfate, fendizoate, fosfatex, fumarate, gluceptate, gluconate,glucuronate, glutamate, glycerophosphate, glysinate,glycollylarsinilate, glycyrrhizate, hippurate, hemisulfate,hexylresorcinate, hybenzate, hydrobromide, hydrochloride, hydroiodid,hydroxybenzenesulfonate, hydroxybenzoate, hydroxynaphthoate, hyclate,iodide, isethionate, lactate, lactobionate, lysine, malate, maleate,mesylate, methylbromide, methyliodide, methylnitrate, methylsulfate,monophosadenine, mucate, napadisylate, napsylate, nicotinate, nitrate,oleate, orotate, oxalate, oxoglurate, pamoate, pantothenate, pectinate,phenylethylbarbiturate, phosphate, pacrate, plicrilix, polistirex,polygalacturonate, propionate, pyridoxylphosphate, saccharinate,salicylate, stearate, succinate, stearylsulfate, subacetate, succinate,sulfate, sulfosalicylate, tannate, tartrate, teprosilate, terephthalate,teoclate, thiocyante, tidiacicate, timonacicate, tosylate, triethiodide,triethiodide, undecanoate, and xinafoate. The approved cations includeammonium, benethamine, benzathine, betaine, calcium, carnitine,clemizole, chlorcyclizine, choline, dibenylamine, diethanolamine,diethylamine, diethylammonium diolamine, eglumine, erbumine,ethylenediamine, heptaminol, hydrabamine, hydroxyethylpyrrolidone,imadazole, meglumine, olamine, piperazine, 4-phenylcyclohexylamine,procaine, pyridoxine, triethanolamine, and tromethamine. Metalliccations include, aluminum, bismuth, calcium lithium, magnesium,neodymium, potassium, rubidium, sodium, strontium and zinc.

A particular class of salts can be classified as organic amine salts.The organic amines used to form these salts can be primary amines,secondary amines or tertiary amines, and the substituents on the aminecan be straight, branched or cyclic groups, including ringed structuresformed by attachment of two or more of the amine substituents. Ofparticular interest are organic amines that are substituted by one ormore, hydroxyalkyl groups, including alditol or carbohydrate moieties.These hydroxy substituted organic amines can be cyclic or acyclic, bothclasses of which can be primary amines, secondary amines or tertiaryamines. A common class of cyclic hydroxy substituted amines are theamino sugars.

Carbohydrate moieties that can comprise one or more substituents in theamine salt include those made from substituted and unsubstitutedmonosaccharides, disaccharides, oligosaccharides, and polysaccharides.The saccharide can be an aldose or ketose, and may comprise 3, 4, 5, 6,or 7 carbons. In one embodiment the carbohydrates are monosaccharides.In another embodiment the carbohydrates are pyranose and furanosesugars. Non limiting examples of pyranose and furanose moieties that canbe part of the organic amine salt include threose, ribulose, ketose,gentiobiose, aldose, aldotetrose, aldopentose, aldohexose, ketohexose,ketotetrose, ketopentose, erythrose, threose, ribose, deoxyribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose,idose, glactose, talose, erythrulose, ribulose, xylulose, psicose,fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose,cellulose, aldose, amylose, palatinose, trehalose, turanose, cellobiose,amylopectin, glucosamine, mannosamine, fucose, phamnose, glucuronate,gluconate, glucono-lactone, muramic acid, abequose, rhamnose, gluconicacid, glucuronic acid, and galactosamine. The carbohydrate moiety canoptionally be deoxygenated at any corresponding C-position, and/orsubstituted with one or more moieties such as hydrogen, halo, haloalkyl,carboxyl, acyl, acyloxy, amino, amido, carboxyl-derivatives, alkylamino,dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester,carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester,thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, orany other viable functional group that does not inhibit thepharmacological activity of this compound. Exemplary substituentsinclude amine and halo, particularly fluorine. The substituent orcarbohydrate can be either unprotected, or protected as necessary, asknown to those skilled in the art, for example, as taught in Greene, etal., Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991, hereby incorporated by reference. In one embodiment themonosaccharide is a furanose such as (L or D)-ribose.

Of particular interest among the acyclic organic amines are a classrepresented by the formula

wherein Y and Z are independently hydrogen or lower alkyl or, may betaken together to form a ring, R is hydrogen, alkyl orhydroxyloweralkyl, and n is 1, 2, 3, 4, or 5. Among these hydroxylaminesare a particular class characterized when n is 4. A representative ofthis group is meglumine, represented when Y is hydrogen, Z is methyl andR is methoxy. Meglumine is also known in the art as N-methylglucamine,N-MG, and 1-deoxy-1-(methylamino)-D-glucitol.

The invention also includes pharmaceutically acceptable prodrugs of thecompounds. Pharmaceutically acceptable prodrugs refer to a compound thatis metabolized, for example hydrolyzed or oxidized, in the host to formthe compound of the present invention. Typical examples of prodrugsinclude compounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound.

Any of the compounds described herein can be administered as a prodrugto increase the activity, bioavailability, stability or otherwise alterthe properties of the compound. A number of prodrug ligands are known.In general, alkylation, acylation or other lipophilic modification ofthe compound will increase the stability of the chalcone. Examples ofsubstituent groups that can replace one or more hydrogens on thecompound are alkyl, aryl, steroids, carbohydrates, including sugars,1,2-diacylglycerol and alcohols. Many are described in R. Jones and N.Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can beused in combination with the disclosed compounds to achieve a desiredeffect.

The compounds can be used to treat inflammatory disorders that aremediated by VCAM-1 including, but not limited to arthritis, asthma,dermatitis, psoriasis, cystic fibrosis, post transplantation late andchronic solid organ rejection, multiple sclerosis, systemic lupuserythematosis, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis,chronic obstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, conjunctivitis, atherosclerosis,coronary artery disease, angina and small artery disease.

The compounds disclosed herein can be used in the treatment ofinflammatory skin diseases that are mediated by VCAM-1, and inparticular, human endothelial disorders that are mediated by VCAM-1,which include, but are not limited to, psoriasis, dermatitis, includingeczematous dermatitis, and Kaposi's sarcoma, as well as proliferativedisorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can beselected to treat anti-inflammatory conditions that are mediated bymononuclear leucocytes.

In yet another embodiment, the compounds of the present invention can beselected for the prevention or treatment of tissue or organ transplantrejection. Treatment and prevention of organ or tissue transplantrejection includes, but are not limited to treatment of recipients ofheart, lung, combined heart-lung, liver, kidney, pancreatic, skin,spleen, small bowel, or corneal transplants. They are also indicated forthe prevention or treatment of graft-versus-host disease, whichsometimes occurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are usefulin both the primary and adjunctive medical treatment of cardiovasculardisease. The compounds are used in primary treatment of, for example,coronary disease states including atherosclerosis, post- angioplastyrestenosis, coronary artery diseases and angina. The compounds can beadministered to treat small vessel disease that is not treatable bysurgery or angioplasty, or other vessel disease in which surgery is notan option. The compounds can also be used to stabilize patients prior torevascularization therapy.

In another aspect the invention provides pharmaceutical compositions forthe treatment of diseases or disorders mediated by VCAM-1 wherein suchcompositions comprise a VCAM-1 inhibiting amount of a chalconederivatives of the invention or a pharmaceutically acceptable saltthereof and/or a pharmaceutically acceptable carrier.

In another aspect invention provides a method for treating a disease ordisorder mediated by VCAM-1 comprising administering to a patient aVCAM-1 inhibiting effective amount of a compound of the invention or apharmaceutically acceptable salt thereof.

In another aspect the invention provides a method for treatingcardiovascular and inflammatory disorders in a patient in need thereofcomprising administering to said patient an VCAM-1 inhibiting effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt thereof.

In another aspect the invention provides a method and composition fortreating asthma or arthritis in a patient in need thereof comprisingadministering to said patient an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be used to treat any disorderthat is mediated by VCAM-1. VCAM-1 is upregulated in a wide variety ofdisease states, including but not limited to arthritis, asthma,dermatitis, psoriasis, cystic fibrosis, post transplantation late andchronic solid organ rejection, multiple sclerosis, systemic lupuserythematosis, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis,chronic obstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, atherosclerosis, coronary arterydisease, angina, small artery disease, and conjunctivitis.

Nonlimiting examples of arthritis include rheumatoid (such assoft-tissue rheumatism and non-articular rheumatism, fibromyalgia,fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis,frozen shoulder, Tietze's syndrome, fascitis, tendinitis, tenosynovitis,bursitis), juvenile chronic, spondyloarthropaties (ankylosingspondylitis), osteoarthritis, hyperuricemia and arthritis associatedwith acute gout, chronic gout and systemic lupus erythematosus.

Human endothelial disorders mediated by VCAM-1 include psoriasis,eczematous dermatitis, Kaposi's sarcoma, as well as proliferativedisorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can beselected to treat anti-inflammatory conditions that are mediated bymononuclear leucocytes.

In one embodiment, the compounds of the present invention are selectedfor the prevention or treatment of tissue or organ transplant rejection.Treatment and prevention of organ or tissue transplant rejectionincludes, but are not limited to treatment of recipients of heart, lung,combined heart-lung, liver, kidney, pancreatic, skin, spleen, smallbowel, or corneal transplants. The compounds can also be used in theprevention or treatment of graft-versus- host disease, such as sometimesoccurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are usefulin both the primary and adjunctive medical treatment of cardiovasculardisease. The compounds are used in primary treatment of, for example,coronary disease states including atherosclerosis, post- angioplastyrestenosis, coronary artery diseases and angina. The compounds can beadministered to treat small vessel disease that is not treatable bysurgery or angioplasty, or other vessel disease in which surgery is notan option. The compounds can also be used to stabilize patients prior torevascularization therapy.

In addition to inhibiting the expression of VCAM-1, some of thecompounds of the invenion have the additional properties of inhibitingmonocyte chemoattractant protein-i (MCP-1) and/or smooth muscleproliferation. MCP-1 is a chemoattractant protein produced byendothelial cells, smooth muscle cells as well as macrophages. MCP-1promotes integrin activation on endothelial cells thereby facilitatingadhesion of leukocytes to VCAM-1, and MCP-1 is a chemoattractant formonocytes. MCP-1 has been shown to play a role in leukocyte recruitmentin a number of chronic inflammatory diseases including atherosclerosis,rheumatoid arthritis, and asthma. Its expression is upregulated in thesediseases and as such inhibition of MCP-1 expression represents adesirable property of anti-inflammatory therapeutics. Furthermore,smooth muscle cell hyperplasia and resulting tissue remodeling anddecreased organ function is yet another characteristic of many chronicinflammatory diseases including atherosclerosis, chronic transplantrejection and asthma. Inhibition of the hyperproliferation of smoothmuscle cells is another desirable property for therapeutic compounds.

Combination and Alternation Therapy

Any of the compounds disclosed herein can be administered in combinationor alternation with a second biologically active agent to increase itseffectiveness against the target disorder.

In combination therapy, effective dosages of two or more agents areadministered together, whereas during alternation therapy an effectivedosage of each agent is administered serially. The dosages will dependon absorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions.

The efficacy of a drug can be prolonged, augmented, or restored byadministering the compound in combination or alternation with a second,and perhaps third, agent that induces a different biological pathwayfrom that caused by the principle drug. Alternatively, thepharmacokinetics, biodistribution or other parameter of the drug can bealtered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the condition.

Any method of alternation can be used that provides treatment to thepatient. Nonlimiting examples of alternation patterns include 1-6 weeksof administration of an effective amount of one agent followed by 1-6weeks of administration of an effective amount of a second agent. Thealternation schedule can include periods of no treatment. Combinationtherapy generally includes the simultaneous administration of aneffective ratio of dosages of two or more active agents.

Illustrative examples of specific agents that can be used in combinationor alternation with the compounds of the present invention are describedbelow in regard to asthma and arthritis. The agents set out below orothers can alternatively be used to treat a host suffering from any ofthe other disorders listed above or that are mediated by VCAM-1 orMCP-1. Illustrative second biologically active agents for the treatmentof cardiovascular disease are also provided below.

Asthma

In one embodiment, the compounds of the present invention areadministered in combination or alternation with heparin, frusemide,ranitidine, an agent that effects respiratory function, such as DNAase,or immunosuppressive agents, IV gamma globulin, troleandomycin,cyclosporin (Neoral), methotrexate, FK-506, gold compounds such asMyochrysine (gold sodium thiomalate), platelet activating factor (PAF)antagonists such as thromboxane inhibitors, leukotriene-D₄-receptorantagonists such as Accolate (zafirlukast), Ziflo (zileuton),leukotriene C₁ or C₂ antagonists and inhibitors of leukotriene synthesissuch as zileuton for the treatment of asthma, or an inducible nitricoxide synthase inhibitor.

In another embodiment, the active compound is administered incombination or alternation with one or more other prophylactic agent(s).Examples of prophylactic agents that can be used in alternation orcombination therapy include but are not limited to sodium cromoglycate,Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom),Tilade (nedocromiil, nedocromil sodium) and ketotifen.

In another embodiment, the active compound is administered incombination or alternation with one or more other O₂-adrenergicagonist(s) (p agonists). Examples of β₂-adrenergic agonists (β agonists)that can be used in alternation or combination therapy include but arenot limited to albuterol (salbutamol, Proventil, Ventolin), terbutaline,Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol(Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutalinesulfate), Tomalate (bitolterol), isoprenaline, ipratropium bromide,bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterolhydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride,efirmoterol fumarate, ephedra (source of alkaloids), ephedrine(ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride,ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenalinehydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol,methoxyphenamine hydrochloride, methylephedrine hydrochloride,orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine(phenylpropanolamine polistirex, phenylpropanolamine sulphate),pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride,psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate,psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterolhydrochloride, rimiterol hydrobromide, ritodrine hydrochloride,salmeterol xinafoate, terbutatine sulphate, tretoquinol hydrate andtulobuterol hydrochloride.

In another embodiment, the active compound is administered incombination or alternation with one or more other corticosteriod(s).Examples of corticosteriods that can be used in alternation orcombination therapy include but are not limited to glucocorticoids (GC),Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide),Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone),Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline,Alclometasone Dipropionate, Aldosterone, Amcinonide, BeclomethasoneDipropionate, Bendacort, Betamethasone (Betamethasone Acetate,Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone SodiumPhosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, ClocortolonePivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort,Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide,Desoxymethasone, Dexamethasone (Dexamethasone Acetate, DexamethasoneIsonicotinate, Dexamethasone Phosphate, Dexamethasone SodiumMetasulphobenzoate, Dexamethasone Sodium Phosphate), DichlorisoneAcetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate,Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide,Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate),Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl,Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate),Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate,Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal,Halcinonide, Halobetasol Propionate, Halometasone, HydrocortamateHydrochloride, Hydrocortisone (Hydrocortisone Acetate, HydrocortisoneButyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone(Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate,Methylprednisolone Sodium Succinate), Mometasone Furoate, ParamethasoneAcetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone(Prednisolone Acetate, Prednisolone Hemisuccinate, PrednisoloneHexanoate, Prednisolone Pivalate, Prednisolone SodiumMetasulphobenzoate, Prednisolone Sodium Phosphate, Prednisb lone SodiumSuccinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone(Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, SuprarenalCortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,Triamcinolone Diacetate and Triamcinolone Hexacetonide).

In another embodiment, the active compound is administered incombination or alternation with one or more other antihistimine(s) (H₁receptor antagonists). Examples of antihistimines (H₁ receptorantagonists) that can be used in alternation or combination therapyinclude alkylamines, ethanolamines ethylenediamines, piperazines,piperidines or phenothiazines. Some non-limiting examples ofantihistimes are Chlortrimeton (Teldrin, chlorpheniramine), Atrohist(brompheniramine, Bromarest, Bromfed, Dimetane), Actidil (triprolidine),Dexchlor (Poladex, Polaramine, dexchlorpheniramine), Benadryl(diphenhydramine), Tavist (clemastine), Dimetabs (dimenhydrinate,Dramamine, Marmine), PBZ (tripelennamine), pyrilamine, Marezine(cyclizine), Zyrtec (cetirizine), bydroxyzine, Antivert (meclizine,Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin(loratadine), Seldane (terfenadine), Periactin (cyproheptadine),Nolamine (phenindamine, Nolahist), Phenameth (romethazine, Phenergan),Tacaryl (methdilazine) and Temaril (trimeprazine).

Alternatively, the compound of the present invention is administered incombination or alternation with

-   (a) xanthines and methylxanthines, such as Theo-24 (theophylline,    Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl    (oxitriphylline), aminophylline;-   (b) anticholinergic agents (antimuscarinic agents) such as    belladonna alkaloids, Atrovent (ipratropium bromide), atropine,    oxitropium bromide;-   (c) phosphodiesterase inhibitors such as zardaverine;-   (d) calcium antagonists such as nifedipine; or-   (e) potassium activators such as cromakalim for the treatment of    asthma.    Arthritic Disorders

In one embodiment, the compound of the present invention can also beadministered in combination or alternation with apazone, amitriptyline,chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine,pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate),misoprostol, paracetamol, superoxide dismutase mimics, TNFα receptorantagonists, TNFα antibodies, P38 Kinase inhibitors, tricyclicantidepressents, cJun kinase inhibitors or immunosuppressive agents, IVgamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate,FK-506, gold compounds such as Myochrysine (gold sodium thiomalate),platelet activating factor (PAF) antagonists such as thromboxaneinhibitors, and inducible nitric oxide sythase inhibitors.

In another embodiment, the active compound is administered incombination or alternation with one or more other corticosteriod(s).Examples of corticosteriods that can be used in alternation orcombination therapy include but are not limited to glucocorticoids (GC),Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide),Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone),Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline,Alclometasone Dipropionate, Aldosterone, Amcinonide, BeclomethasoneDipropionate, Bendacort, Betamethasone (Betamethasone Acetate,Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone SodiumPhosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, ClocortolonePivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort,Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide,Desoxymethasone, Dexamethasone (Dexamethasone Acetate, DexamethasoneIsonicotinate, Dexamethasone Phosphate, Dexamethasone SodiumMetasulphobenzoate, Dexamethasone Sodium Phosphate), DichlorisoneAcetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate,Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide,Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate),Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl,Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate),Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate,Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal,Halcinonide, Halobetasol Propionate, Halometasone, HydrocortamateHydrochloride, Hydrocortisone (Hydrocortisone Acetate, HydrocortisoneButyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone(Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate,Methylprednisolone Sodium Succinate), Mometasone Furoate, ParamethasoneAcetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone(Prednisolone Acetate, Prednisolone Hemisuccinate, PrednisoloneHexanoate, Prednisolone Pivalate, Prednisolone SodiumMetasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone SodiumSuccinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone(Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, SuprarenalCortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,Triamcinolone Diacetate and Triamcinolone Hexacetonide).

In another embodiment, the active compound is administered incombination or alternation with one or more other non-steroidalanti-inflammatory drug(s) (NSAIDS). Examples of NSAIDS that can be usedin alternation or combination therapy are carboxylic acids, propionicacids, fenamates, acetic acids, pyrazolones, oxicans, alkanones, goldcompounds and others that inhibit prostaglandin synthesis, preferably byselectively inhibiting cylcooxygenase-2 (COX-2). Some nonlimitingexamples of COX-2 inhibitors are Celebrex (celecoxib), Bextra(valdecoxib), Dynastat (parecoxib sodium) and Vioxx (rofacoxib). Somenon-limiting examples of NSAIDS are aspirin (acetylsalicylic acid),Dolobid (diflunisal), Disalcid (salsalate, salicylsalicylate), Trisilate(choline magnesium trisalicylate), sodium salicylate, Cuprimine(penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil, NuprinRufen), Naprosyn (naproxen, Anaprox, naproxen sodium), Nalfon(fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen), Daypro(oxaprozin), meclofenamate (meclofanamic acid, Meclomen), mefenamicacid, Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren(diclofenac), Lodine (etodolac), ketorolac, Butazolidin(phenylbutazone), Tandearil (oxyphenbutazone), piroxicam (Feldene),Relafen (nabumetone), Myochrysine (gold sodium thiomalate), Ridaura(auranofin), Solganal (aurothioglucose), acetaminophen, colchicine,Zyloprim (allopurinol), Benemid (probenecid), Anturane (sufinpyrizone),Plaquenil (hydroxychloroquine), Aceclofenac, Acemetacin, Acetanilide,Actarit, Alclofenac, Alminoprofen, Aloxiprin, Aluminium Aspirin, AmfenacSodium, Amidopyrine, Aminopropylone, Ammonium Salicylate, Ampiroxicam,Amyl Salicylate, Anirolac, Aspirin, Auranofin, Aurothioglucose,Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine), Benorylate,Benoxaprofen, Benzpiperylone, Benzydamine, Hydrochloride, BornylSalicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium, ButibufenSodium, Capsaicin, Carbaspirin Calcium, Carprofen, Chloithenoxazin,Choline Magnesium Trisalicylate, Choline Salicylate, Cinmetacin,Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene,Diacerein, Diclofenac (Diclofenac Diethylammonium Salt, DiclofenacPotassium, Diclofenac Sodium), Diethylamine Salicylate,Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam,Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac,Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium,Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic,Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen,Glafenine, Glucametacin, Glycol Salicylate, Gold Keratinate,Harpagophytum Procumbens, Ibufenac, Ibuprofen, Ibuproxam, ImidazoleSalicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone,Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, LithiumSalicylate, Lonazolac Calcium, Lomoxicam, Loxoprofen Sodium, LysineAspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid,Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate,Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, MorazoneHydrochloride, Momiflurnate, Morpholine Salicylate, Nabumetone, Naproxen(Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide, Oxametacin,Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone,Phenyramidol Hydrochloride, Picenadol Hydrochloride, PicolamineSalicylate, Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen,Pranosal, Proglumetacin Maleate, Proquazone, Protizinic Acid,Ramifenazone, Salacetamide, Salamidacetic Acid, Salicylamide, Salix,Salol, Salsalate, Sodium Aurothiomalate, Sodium Gentisate, SodiumSalicylate, Sodium Thiosalicylate, Sulindac, Superoxide Dismutase(Orgotein, Pegorgotein, Sudismase), Suprofen, Suxibuzone, TenidapSodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate, Tiaprofenic,Tiaramide Hydrochloride, Tinoridine Hydrochloride, Tolfenamic Acid,Tometin Sodium, Triethanolamine Salicylate, Ufenamate, Zaltoprofen,Zidometacin and Zomepirac Sodium.

Cardiovascular Disease

Compounds useful for combining with the compounds of the presentinvention for the treatment of cardiovascular disease encompass a widerange of therapeutic compounds.

Ileal bile acid transporter (IBAT) inhibitors, for example, are usefulin the present invention, and are disclosed in patent application no.PCT/US95/10863, herein incorporated by reference. More IBAT inhibitorsare described in PCT/US97/04076, herein incorporated by reference. Stillfurther IBAT inhibitors useful in the present invention are described inU.S. application Ser. No. 08/816,065, herein incorporated by reference.More IBAT inhibitor compounds useful in the present invention aredescribed in WO 98/40375, and WO 00/38725, herein incorporated byreference. Additional IBAT inhibitor compounds useful in the presentinvention are described in U.S. application Ser. No. 08/816,065, hereinincorporated by reference.

In another aspect, the second biologically active agent is a statin.Statins lower cholesterol by inhibiting of 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase, a key enzyme in the cholesterolbiosynthetic pathway. The statins decrease liver cholesterolbiosynthesis, which increases the production of LDL receptors therebydecreasing plasma total and LDL cholesterol (Grundy, S. M. New Engl. J.Med. 319, 24 (1988); Endo, A. J. Lipid Res. 33, 1569 (1992)). Dependingon the agent and the dose used, statins may decrease plasma triglyceridelevels and may increase HDLc. Currently the statins on the market arelovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb)and fluvastatin (Sandoz). A fifth statin, atorvastatin(Parke-Davis/Pfizer), is the most recent entrant into the statin market.Any of these statins or thers can be used in combination with thechalcones of the present invention.

MTP inhibitor compounds useful in the combinations and methods of thepresent invention comprise a wide variety of structures andfunctionalities. Some of the MTP inhibitor compounds of particularinterest for use in the present invention are disclosed in WO 00/38725,the disclosure from which is incorporated by reference. Descriptions ofthese therapeutic compounds can be found in Science, 282, 23 Oct. 1998,pp. 751-754, herein incorporated by reference.

Cholesterol absorption antagonist compounds useful in the combinationsand methods of the present invention comprise a wide variety ofstructures and functionalities. Some of the cholesterol absorptionantagonist compounds of particular interest for use in the presentinvention are described in U.S. Pat. No. 5,767,115, herein incorporatedby reference. Further cholesterol absorption antagonist compounds ofparticular interest for use in the present invention, and methods formaking such cholesterol absorption antagonist compounds are described inU.S. Pat. No. 5,631,365, herein incorporated by reference.

A number of phytosterols suitable for the combination therapies of thepresent invention are described by Ling and Jones in “DietaryPhytosterols: A Review of Metabolism, Benefits and Side Effects,” LifeSciences, 57 (3), 195-206 (1995). Without limitation, some phytosterolsof particular use in the combination of the present invention areClofibrate, Fenofibrate, Ciprofibrate, Bezafibrate, Gemfibrozil. Thestructures of the foregoing compounds can be found in WO 00/38725.

Phytosterols are also referred to generally by Nes (Physiology andBiochemistry of Sterols, American Oil Chemists' Society, Champaign,Ill., 1991, Table 7-2). Especially preferred among the phytosterols foruse in the combinations of the present invention are saturatedphytosterols or stanols. Additional stanols are also described by Nes(Id.) and are useful in the combination of the present invention. In thecombination of the present invention, the phytosterol preferablycomprises a stanol. In one preferred embodiment the stanol iscampestanol. In another preferred embodiment the stanol is cholestanol.In another preferred embodiment the stanol is clionastanol. In anotherpreferred embodiment the stanol is coprostanol. In another preferredembodiment the stanol is 22,23-dihydrobrassicastanol. In anotherembodiment the stanol is epicholestanol. In another preferred embodimentthe stanol is fucostanol. In another preferred embodiment the stanol isstigmastanol.

Another embodiment the present invention encompasses a therapeuticcombination of a compound of the present invention and an HDLc elevatingagent. In one aspect, the second HDLc elevating agent can be a CETPinhibitor. Individual CETP inhibitor compounds useful in the presentinvention are separately described in WO 00/38725, the disclosure ofwhich is herein incorporated by reference. Other individual CETPinhibitor compounds useful in the present invention are separatelydescribed in WO 99/14174, EP818448, WO 99/15504, WO 99/14215, WO98/04528, and WO 00/17166, the disclosures of which are hereinincorporated by reference. Other individual CETP inhibitor compoundsuseful in the present invention are separately described in WO 00/18724,WO 00/18723, and WO 00/18721, the disclosures of which are hereinincorporated by reference. Other individual CETP inhibitor compoundsuseful in the present invention are separately described in WO 98/35937as well as U.S. Pat. Nos. 6,313,142, 6,310;075, 6,197,786, 6,147,090,6,147,089, 6,140,343, and 6,140,343, the disclosures of which is hereinincorporated by reference.

In another aspect, the second biologically active agent can be a fibricacid derivative. Fibric acid derivatives useful in the combinations andmethods of the present invention comprise a wide variety of structuresand functionalities which have been reported and published in the art.

In another embodiment the present invention encompasses a therapeuticcombination of a compound of the present invention and anantihypertensive agent. Hypertension is defined as persistently highblood pressure. In another embodiment, the chalcone is administered incombination with an ACE inhibitor, a beta andrenergic blocker, alphaandrenergic blocker, angiotensin II receptor antagonist, vasodilator anddiuretic.

Pharmaceutical Compositions

Any host organism, including a pateint, mammal, and specifically ahuman, suffering from any of the above-described conditions can betreated by the administration of a composition comprising an effectiveamount of the compound of the invention or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier ordiluent.

The composition can be administered in any desired manner, includingoral, topical, parenteral, intravenous, intradermal, intra-articular,intra-synovial, intrathecal, intra-arterial, intracardiac,intramuscular, subcutaneous, intraorbital, intracapsular, intraspinal,intrasternal, topical, transdermal patch, via rectal, vaginal orurethral suppository, peritoneal, percutaneous, nasal spray, surgicalimplant, internal surgical paint, infusion pump, or via catheter. In oneembodiment, the agent and carrier are administered in a slow releaseformulation such as an implant, bolus, microparticle, microsphere,nanoparticle or nanosphere. For standard information on pharmaceuticalformulations, see Ansel, et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Edition, Williams & Wilkins (1995).

An effective dose for any of the herein described conditions can bereadily determined by the use of conventional techniques and byobserving results obtained under analogous circumstances in determiningthe effective dose, a number of factors are considered including, butnot limited to: the species of patient; its size, age, and generalhealth; the specific disease involved; the degree of involvement or theseverity of the disease; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; and the use of concomitant medication. Typicalsystemic dosages for all of the herein described conditions are thoseranging from 0.1 mg/kg to 500 mg/kg of body weight per day as a singledaily dose or divided daily doses. Preferred dosages for the describedconditions range from 5-1500 mg per day. A more particularly preferreddosage for the desired conditions ranges from 25-750 mg per day. Typicaldosages for topical application are those ranging from 0.001 to 100% byweight of the active compound.

The compound is administered for a sufficient time period to alleviatethe undesired symptoms and the clinical signs associated with thecondition being treated.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutic amount of compound in vivo in the absence of serious toxiceffects.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Theactive ingredient may be administered at once, or may be divided into anumber of smaller doses to be administered at varying intervals of time.

A preferred mode of administration of the active compound for systemicdelivery is oral. Oral compositions will generally include an inertdiluent or an edible carrier. They may be enclosed in gelatin capsulesor compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar, shellac, or other enteric agents.

The compound or its salts can be administered as a component of anelixir, suspension, syrup, wafer, chewing gum or the like. A syrup maycontain, in addition to the active compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.

The compound can also be mixed with other active materials that do notimpair the desired action, or with materials that supplement the desiredaction. The compounds can also be administered in combination withnonsteroidal antiinflammatories such as ibuprofen, indomethacin,fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound canalso be administered with corticosteriods.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. pH can be adjusted withacids or bases, such as hydrochloric acid or sodium hydroxide. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) orphosphate buffered saline (TBS).

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) are also preferred as pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811 (which is incorporated herein by reference in its entirety).For example, liposome formulations may be prepared by dissolvingappropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine,stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, andcholesterol) in an inorganic solvent that is then evaporated, leavingbehind a thin film of dried lipid on the surface of the container. Anaqueous solution of the compound is then introduced into the container.The container is then swirled by hand to free lipid material from thesides of the container and to disperse lipid aggregates, thereby formingthe liposomal suspension.

Suitable vehicles or carriers for topical application can be prepared byconventional techniques, such as lotions, suspensions, ointments,creams, gels, tinctures, sprays, powders, pastes, slow-releasetransdermal patches, suppositories for application to rectal, vaginal,nasal or oral mucosa. In addition to the other materials listed abovefor systemic administration, thickening agents, emollients andstabilizers can be used to prepare topical compositions. Examples ofthickening agents include petrolatum, beeswax, xanthan gum, orpolyethylene, humectants such as sorbitol, emollients such as mineraloil, lanolin and its derivatives, or squalene.

Any of the compounds described herein for combination or alternationtherapy can be administered as any derivative that upon administrationto the recipient, is capable of providing directly or indirectly, theparent compound, or that exhibits activity itself. Nonlimiting examplesare the pharmaceutically acceptable salts (alternatively referred to as“physiologically acceptable salts”), and a compound which has beenalkylated or acylated at an appropriate position. The modifications canaffect the biological activity of the compound, in some cases increasingthe activity over the parent compound. This can easily be assessed bypreparing the derivative and testing its anti-inflammatory activityaccording to known methods.

Biological Activity of Active Compounds

The ability of a compound described herein to inhibit the expression ofVCAM-1 or in the treatment of diseases in a host can be assessed usingany known method, including that described in detail below.

In Vitro MCP-1 Activity Assay

Cultured human endothelial cells were seeded in 96-well plates. On thefollowing day cells were stimulated with TNF-α (1 ng/ml) in the presenceor absence of compounds dissolved in DMSO. To establish a dose curve anIC₅₀, multiple concentrations in 2- to 5-fold increments were used.Cells were exposed to TNF-α and compounds for approximately 16 hours.The next day the cells were visually examined via light microscopy toscore for visual signs of toxicity. Cell culture media, diluted 1:10,was analyzed by an MCP-1 immunoassay kit (R & D Systems). This assay isa sandwich immunoassay using immobilized anti-MCP-1 antibody in 96-wellplate to capture secreted MCP-1 in cell culture media. Captured MCP-1was subsequently detected with a horse radish peroxidase-conjugatedanti-MCP-1 antibody for color development. Compound 3 expressed an IC₅₀values of >10(the amount of compound (μM) required to achieve a 50%reduction compared to control (cells stimulated with TNF-α only)).

In Vitro VCAM-1 Assay

Cell Culture and compound dosing: Cultured primary human aortic (HAEC)or pulmonary (HPAEC) endothelial cells were obtained from Clonetics,Inc., and were used below passage 9. Cells were seeded in 96 well platessuch that they would reach 90-95% confluency by the following day. Onthe following day the cells were stimulated with TNF-α (1 ng/ml) in thepresence or absence of compounds dissolved in DMSO such that the finalconcentration of DMSO is 0.25% or less. To establish a dose curve foreach compound, four concentrations in 2- to 5-fold increments were used.Cells were exposed to TNF-α and compounds for approximately 16 hours.The next day the cells were examined under microscope to score forvisual signs of toxicity or cell stress.

Following 16 hr exposure to TNF-α and compound the media was discardedand the cells were washed once with Hanks Balanced Salt Solution(HBSS)/Phosphate buffered saline (PBS) (1:1). Primary antibodies againstVCAM-1 (0.251 g/ml in HBSS/PBS+5% FBS) were added and incubated for30-60 minutes at 37° C. Cells were washed with HBSS/PBS three times, andsecondary antibody Horse Radish Peroxidase (HRP)-conjugated goatanti-mouse IgG (1:500 in HBSS/PBS+5% FBS) were added and incubated for30 minutes at 37° C. Cells were washed with HBSS/PBS four time and TMBsubstrate were added and incubated at room temperature in the dark untilthere was adequate development of blue color. The length of time ofincubation was typically 5-15 minutes. 2N sulfuric acid was added tostop the color development and the data was collected by reading theabsorbance on a BioRad ELISA plate reader at OD 450 nm. The results areexpressed as IC₅₀ values (the concentration (micromolar) of compoundrequired to inhibit 50% of the maximal response of the control samplestimulated by TNF-α only). Compounds exhibiting IC₅₀'s of less than 5micromolar are tabulated in Biological Table 1. Biological Table 1VCAM-1 Example IC50 Number (μM) 1 <1 2 <5 3 <1 4 <10 5 <1 6 <1 7 <1 8 <19 <5 10 <5 11 <5 12 <5 13 <5 14 <1 15 >10 16 <5 17 <5 18 <5 19 <1 20 >1021 <5 22 >10 23 <1 24 >10 25 >10 26 >10 27 <5 28 <5 29 <1 30 <1 31 >1032 <5 33 <5 34 >10 35 >10 36 <5 37 >10 38 <10 39 >10 40 <1 41 <5 42 <543 <5 44 <1 45 <5 46 <10 47 >10 48 <10 49 <10 50 >10 51 <5 52 >10 53 <554 <10 55 <5 56 <1 57 <5 58 >10 59 NE 60 <1 61 <1 62 <5 63 <10 64 >10 65<1 66 <1 67 <10 68 <5 69 <5 70 <5 71 NE 72 0 73 0 74 >10 75 >10 76 >1077 <5 78 <10 79 <1 80 <5 81 <1 82 NE 83 <1 84 <5 85 <1 86 <5 87 <1 88 89NE 90 <1 91 <5 92 <1 93 <1 94 <1 95 <1 96 <5 97 NE 98 <5 99 >10 100 >10101 >10 102 >10 103 >10 104 NE 105 NE 106 <10 107 NE 108 <10 109 NE110 >10 111 >10 112 NE 113 <5 114 <5 115 <5 116 117 <5 118 <10 119 120<1Rheumatoid Arthritis Protocol

Male Lewis rats (150-175 g) from Charles River Laboratories wereanesthetized on day 0 with 3-5% isoflurane anesthesia while the tailbase was shaved and adjuvant mixture was injected. Fifty μL of adjuvant(10 mg/ml M. butyricum in mineral oil) was injected subcutaneously intotwo sites at the tail base. Paw swelling was monitored using aplethysmometer (UGO Basile), after shaving each leg to the level of theAchilles tendon to mark the level of immersion. A baseline pawmeasurement for both hindpaws was taken between d2-d5 and a secondmeasurement was taken on day 7-8. Onset of paw swelling occurred rapidlybetween d9-11 and daily measurements were performed every weekdaybetween d9 and day 15. Compounds of the invention and vehicles weredosed either prophylactically (d1-14), or therapeutically (d9-14) afterswelling was confirmed. Solutions were injected subcutaneously or givenorally by gavage 1-2 times per day. From day 0, rats were weighed every2-3 days and overall health was monitored. Plasma drug levels, ifdesired, were measured in tail-vein derived blood samples taken on day14. On day 15, blood samples were obtained by cardiac puncture, ratswere euthanized with CO₂, selected organs removed and both hindpaws wereamputated and placed in 10% buffered formalin for histopathologicalanalysis. See Biological Table 2. Biological Table 2 Compound Example %Inhibition 60 mg/Kg/day, Number sq, bid, d1-14 3 96 6 77 29 82 60  62**75 mg/kg/day, sq, bid, d1-14Asthma Protocol

Balb/C mice (6-8 weeks old) are sensitized to ovalbumin (ova) (8 ug ovaabsorbed in 3.3 mg Alum inject) on days 0 and 5. On day 12, the micewere aerosol challenged with 0.5% ovalbumin dissolved in sterile salinefor 1 hr in the AM, and then again in the PM (at least 4 hr apart). Onday 14, the mice were anesthetized with ketamine/xylazine/acepromazinecocktail, exsanguinated, and then euthanized. Following bloodcollection, bronchoaveolar lavage was performed on each animal. Totalcell counts were conducted on the lavage fluid, which was subsequentlydiluted with cell media 1:1. Slides of the lavage fluid were made byspinning the samples with a cytospin centrifuge. Slides were airdriedand stained with x. Cell differentials of the lavage fluid werecompleted at the conclusion of the study. All compounds except Example 2were well tolerated with no body weight loss throughout the course ofthe study. Statistical analysis involved ANOVA and Tukey-Kramer post hoctests. Compounds were administered except where noted by subcutaneousinjection once daily from day 0-13. The formulations used containedvarious mixtures of the following excipients (pharmasolve, cremdphor RH40, tween 80, PEG 300). See Biological Table 3 Biological Table 3 %Inhibition sc, daily dosing at 100 mg/kg Compound Example Number fromday 0-13 3 79 6 81 86 48 36 71 60 36 29 24Effect of Serum IgE Levels in Ovalbumin Sensitized Balb/c Mice

Peripheral blood samples were collected from ovalbumin (Calbiochem) orvehicle (2% Cremophor/Bicarbonate) treated Balb/c mice (Charles River)with or without administration of test compound (100 mg/kg/d, from day 0to day 14). Serum was obtained by centrifugation and transferred intoMicrotainer serum tubes and frozen at −80° C. Mouse IgE ELISAQuantitation Kit (Bethyl Laboratories, Inc. Montgomery, Tex. orPharMingen, San Diego, Calif.) was applied to measure the IgE levels ofserum samples. Immuno-reactions were performed as Kit protocol with IgEstandard and serum samples in duplicates. The results were read in amicroplate reader (Bio-Rad Model 550) at 450 nm and the amounts of IgEwere calculated according to the standard curve. The limit of detectionin our experiments was 7 ng/ml. Compound 3 administrated at 100 mg/kg/dfrom day 0 to day 14, reduced serum IgE levels by 38% in ovalbuminsensitized Balb/c mice compared with vehicle treated mice.

Effect of Levels of IL-13, IL-5, IL-4, IFN-gamma and IL-2 mRNA in MouseLungs of Balb/c Mice with Ovalbumin Sensitization and Challenge

Lung tissues were collected from ovalbumin (Calbiochem) or vehicle (2%Cremophor/Bicarbonate) sensitized Balb/c mice (Charles River) with orwithout treatment of test compound (100 mg/kg/d, from day 0 to day 14).Total RNA samples were isolated by the Trizol method: (LifeTechnologies, Grand Island, N.Y.) and quantitatively measured by UVspectrophotometer, as well as qualitatively examined by ethidum bromidestained gel electrophoresis. First strand cDNA templates were generatedwith oligo (dT) by Reverse Transcription Kit (invitrogen, Carlsbad,Calif.). The initial amounts of mRNA of each samples were quantitativelydetermined by running a SYBR Green (Qiagen, Valencia, Calif.) basedreal-time PCR (programmed as: initial denaturation at 95° C. for 15minutes, denaturation at 95° C. for 15 seconds, annealing and elongationat 51±1° C. for 1 minute for total 40 cycles) with a specific pair ofprimers (IDT Corporation, Coralville, Iowa) and control primers forGAPDH in iCycler IQ Optical System (Hercules, Calif.). The data werestatistically analyzed by ANOVA and t-tests with multiple comparisons ofmeans (n=5 and P<0.05 were considered significant). Compound 3administrated at 100 mg/kg/d, significantly inhibited ovalbumin inducedlevels of IL-13, IL-5 and IL-4 mRNA in the lung of Balb/c mice by 82%,98% and 68% respectively; without significantly affecting IFN-gamma andIL-2 compared with vehicle treated mice.

List of Primers Used in Above Experiments: Primer Annealing Name ForwardSequence Reverse Sequence Temperature GAPDH CTA CCC CCA ATG CTG CTT CACCAC 52.2 TGT CC CTT CTT IL-13 AAF AFF AGA GCA CTG TGT AAC CTT 51.3 AATGAA AG CCC AAC A IL-4 TGA ATG AGT CCA AGC ATG GTG GCT 51.2 AGT CCA CAGTA IL5 AGC TCT GTT GAC CCC TGA AAG ATT 52.4 AAG CAA T TCT CCA ATG IL-2GTC GAC TTT CTG ATG TGT TGT AAG 53.2 AGG AGA TG CAG GAG GT IFN-γ TTC TGTCTC CTC CAA TCA CAG TCT 51.3 AAC TAT TTC T TGG CTA ATSmooth Muscle Cell Proliferation Protocol

Human Aortic Smooth Mucle Cells (HAoSMC) were obtained from Clonetics,Inc. and were used below passage 10. Cells were seeded in 24-wellplates. When cells were 80% confluent, they were made quiescent byadding media containing 0.2% serum (as compared to 5% serum in normalculture media) for 48 hours. The cells were, then, stimulated by 5%serum in the presence or absence of compounds dissolved in DMSO. Toestablish a dose curve and IC₅₀ for each compound, multipleconcentrations in the range of 20 to 0.05 μM were used. Rapamycin (at 1and 0.1 μM) was used as a positive control for the assay. After a 20hour incubation with or without test compounds, 3H-thymidine (0.5μCi/well) was added to the cells for 4 hours of labeling. Washed cellswere then lysed in NaOH and the amount of 3H-thymidine incorporation wasdetermined. Cytotoxicity of the drug was measured by use of the CytolTox96 assay kit (Promega, Madison, Wis.). Compound 3 had an IC₅₀ of 0.5 μM.

Effect of Test Compounds on LPS-Stimulated IL-1β

Human peripheral blood mononuclear cells were treated with or withoutCompound 3 for 1 hour, then stimulated with LPS (1-2 μg/ml) for 3 hours.Condition media was collected and IL-1β measured using an ELISA kit.Compound 3 demonstrated a dose dependent inhibition of LPS-stimulatedIL-1β secretion. See Biological Table 4 Biological Table 4 Amount ofCompound 3 (μM) Percent IL-1β Secreted 1.25 >40 2.5 >10 5 >5 10 >1Reduction of Plasma TNF-α Levels and Lung VCAM-1 mRNA Levels inLPS-Challenged Mice.

Balb/C mice (6-8 weeks) were injected with LPS (1 mg/kg; 5 mls/kg) andsacrificed 2 hr later. Blood was collected for plasma TNF-α levels andlungs for measurement of VCAM-1 mRNA levels by quantitative RT-PCR.Compound 3 administered subcutaneously at a dose of 100 mg/kg/d, 2 hrprior to LPS injection, inhibited TNF-α production by 80% and VCAM-1expression by 60% compared with vehicle controls.

Disease Modifying Anti-Rheumatic Drug (DMARD) Activity in Rat AdjuvantArthritis

Compound 3 at twice daily subcutaneous doses of 60, 40 and 20 mg/kg/dwas found to inhibit bone erosion in the ankle joint byhistopathological analysis when administered prophylactically in the ratadjuvant arthritis model. The evaluation was carried out withhematoxylin and eosin stained ankle cross sections by a certifiedveterinary pathologist. When dosed prophylactically at doses of 100, 50and 25 mg/kg/d, b.i.d., s.c., Compound 3 was also found to inhibitsplenomegaly. Splenomegaly tracks with bone erosion in the adjuvantarthritis model and is thought to be a predictor of DMARDs activity.

Modifications and variations of the present invention relating tocompounds and methods of treating diseases will be obvious to thoseskilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withinthe scope of the appended claims.

1. A compound of Formula I

or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R¹)₂, —OC(R¹)₂C(O)NR⁷ R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(2β), R^(3β), R^(4β), R^(5β) orR^(6β), or one of R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) must be acarbon-carbon linked heterocyclic or heteroaryl; wherein when one ofR^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) is a carbon-carbon linkedheterocyclic or heteroaryl, only one of R^(2α), R^(3α), R^(4α), R^(5α)or R^(6α) can be —OCH₃; wherein when one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) is a carbon-carbon linked heterocyclic or heteroaryl,only one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) can be —OCH₃; withthe proviso that R^(2α) and R^(3α), taken together or R^(3α) and R^(4α),taken together or R^(4α) and R^(5α) taken together, or R^(2β) and R^(3β)taken together or R^(3β) and R^(4β) taken together or R^(4β) and R^(5β)taken together form a heterocyclic or heteroaryl optionally substitutedby one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl oraminoalkyl and optionally substituted with one or more selected from thegroup consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo; orR^(2α) and R^(3α) taken together or R^(3α) and R^(4α), taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH; orat least one of R^(2α), R^(3α), R^(4α), R^(5α), R^(6α) or one of R^(2β),R^(3β), R^(4β), R^(5β), R^(6β) must be selected from the groupconsisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂.
 2. The compound of claim 1or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α) R^(4α), R^(5α), R^(6α, R) ^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R² R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R¹)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(2β), R^(3β), R^(4β), R^(5β) or R⁶² ,or one of R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) must be acarbon-carbon linked heterocyclic or heteroaryl; wherein when one ofR^(2β), R^(3β), R^(4β), R^(5β or R) ^(6β) is a carbon-carbon linkedheterocyclic or heteroaryl, only one of R^(2α), R^(3α), R^(4α), R^(5α)or R^(6α) can be —OCH₃; wherein when one of R^(2α), R^(3α), R^(4α),R^(5α) or R^(6α) is a carbon-carbon linked heterocyclic or heteroaryl,only one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β) can be —OCH₃; withthe proviso that R^(2α) and R^(3α) taken together or R^(3α) and R^(4α)taken together or R^(4α) and R^(5α) taken together, or R^(2β) and R^(3β)taken together or R^(3β) and R^(4β) taken together or R^(4β) and R^(5β)taken together form a heterocyclic or heteroaryl optionally substitutedby one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl oraminoalkyl and optionally substituted with one or more selected from thegroup consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo; orR^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R¹)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH; andat least one of R^(2α) R^(3α), R^(4α), or one of R^(2β), R^(3β), R^(4β)must be selected from the group consisting of cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR²,—C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R²,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH,—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂,—SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂—SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR² SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.
 3. The compound of claim 1or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, andC(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β)must be a carbon-carbon linked heterocyclic or heteroaryl, and only oneof R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with theproviso that R^(2α) and R^(3α) taken together or R^(3α) and R^(4α) takentogether or R^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) takentogether or R^(3β) and R^(4β) taken together or R^(4β) and R^(5β) takentogether form a heterocyclic or heteroaryl optionally substituted by oneor more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyland optionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo; orR^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH; andwith the proviso that at least one of R^(2α), R^(3α), R^(4α), R^(5α), orR^(6α) must be selected from the group consisting of cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R²,—C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4,5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl,alkenyl,-cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂.
 4. The compound of claim 3or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R¹)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso thatR^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR³β and R^(4β) taken together or R^(4β) and R^(5β) taken together form aheterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo; orR^(2α) and R^(3α) taken together of R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(6β) and R^(6β) cannot be —OC(R¹)₂C(O)OH; andwith the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂.
 5. The compound of claim 4or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR² SO₂R², —NHC(O)NHR⁷, —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R¹)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂,—C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein yis 1, 2, 3, 4, 5, or 6, thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR²,—SCH₂C(O)OH—SCF₂C(O)OH—SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸,—SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸,—NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR²,—NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.
 6. The compound of claim 5or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R¹)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6; wherein all R¹, R²,R⁷ and R⁸ substituents can be optionally substituted with one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.
 7. The compound of claim 6or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R¹)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ is independentlyselected from the group consisting of hydrogen, lower alkyl, cycloalkyl,aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,—C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² is independently selected from the groupconsisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6; wherein all R¹, R²,R⁷ and R⁸ substituents can be optionally substituted with one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —(O)N(R²)₂.
 8. The compound of claim 7or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, —C(O)R², R²C(O)alkyl,aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylaminolower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl,polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy,arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, dialkylamino,cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —N(R²)C(O)R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NHC(O)NR⁷R⁸,—NHC(O)N(R²)₂, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R¹)₂, —SO₂NHC(O)NR⁷R⁸, cyano,tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂,—C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂,—C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(CH₃)₂C(O)OH, and —(CH₂)_(y)C(O)OH, wherein y is 1,2, 3, 4, 5, or 6, all of which can be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹is independently selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be optionally substituted by one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² isindependently selected from the group consisting of alkyl, lower alkyl,cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,wherein all may be substituted by one or more selected from the groupconsisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl,hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy,oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6; wherein all R¹, R²,R⁷ and R⁸ substituents can be optionally substituted with one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, —C(O)NR⁷R⁸, and —C(O)N(R²)₂. 9.The compound of claim 8 or its pharmaceutically acceptable salt orester, wherein: R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β),R^(4β), R^(5β) and R^(6β) are independently selected from the groupconsisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl,heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl,hydroxyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl,polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy,heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,heterocyclic lower alkoxy, dialkylamino, N(R²)₂, —NR⁷R⁸, tetrazol-5-yl,carboxy, —C(O)OR, —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(CH₃)₂C(O)OH, and—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R²is independently selected from the group consisting of alkyl, loweralkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,wherein all may be substituted by one or more selected from the groupconsisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ areindependently selected from the group consisting of alkyl, alkenyl andaryl and linked together forming a 4- to 8-membered monocyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of tetrazol-5-yl, carboxy, —C(O)OR², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6; wherein all R², R⁷and R⁸ substituents can be optionally substituted with one or moreselected from the group consisting of halo, lower alkyl, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.10. The compound of claim 9 or its pharmaceutically acceptable salt orester, wherein: R^(2α), R^(3α), R^(4α), R^(5α), R^(6α) R^(2β), R^(3β),R^(4β), R^(5β) and R^(6β) are independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryllower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, loweralkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, heteroaryl loweralkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy,—C(O)OR², —C(O)N(R²)₂, and —C(O)NR⁷R⁸, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic,—NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² is independently selected fromthe group consisting of alkyl, and lower alkyl, wherein all may besubstituted by one or more selected from the group consisting of halo,lower alkyl, —NR⁷R⁸, alkoxy, —C(O)NR⁷R⁸, and —C(O)N(R¹)₂; R⁷ and R⁸ areindependently alkyl, and linked together forming a 5- to 7-memberedmonocyclic or benzofused ring; wherein one of R^(4β), R^(5β) or R^(6β)must be a carbon-carbon linked heterocyclic or heteroaryl, and only oneof R^(2α), R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with theproviso that at least one of R^(2α), R^(3α), or R^(4α) must be selectedfrom carboxy or —C(O)OR²; wherein all R², R⁷ and R⁸ substituents can beoptionally substituted with one or more selected from the groupconsisting of halo, lower alkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.11. The compound of claim 10 or its pharmaceutically acceptable salt orester, wherein: R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β),R^(4β), R^(5β) and R^(6β) are independently selected from the groupconsisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic loweralkoxy, and carboxy, all of which can be optionally substituted by oneor more selected from the group consisting of hydroxy, hydroxyalkyl,—NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² is lower alkyl; R⁷ and R⁸ areindependently alkyl, and linked together forming a 6-membered monocyclicor benzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be carboxy.
 12. The compoundof claim 11 or its pharmaceutically acceptable salt or ester, wherein:R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independently selectedfrom the group consisting of hydrogen and carboxy; R^(2β), R^(3β),R^(4β), R^(5β) and R^(6β) are independently selected from the groupconsisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, and heterocycliclower alkoxy, all of which can be optionally substituted by one or moreselected from the group consisting of hydroxy, hydroxyalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² is lower alkyl; R⁷ and R⁸ areindependently alkyl, and linked together forming a 6-membered monocyclicor benzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl; with the proviso thatat least one of R^(2α), R^(3α), or R^(4α) must be carboxy.
 13. Thecompound of claim 12 or its pharmaceutically acceptable salt or ester,wherein: R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) are independentlyselected from the group consisting of hydrogen and carboxy; R^(2β),R^(3β), R^(4β), R^(5β) and R^(6β) are independently selected from thegroup consisting of hydrogen, halogen, heteroaryl, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryl lower alkoxy, and heterocycliclower alkoxy, all of which can be optionally substituted by one or moreselected from the group consisting of hydroxy, hydroxyalkyl, —NR⁷R⁸,—C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² is lower alkyl; R⁷ and R⁸ areindependently alkyl, and linked together forming a 6-membered monocyclicor benzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heteroaryl; with the proviso that at least one ofR^(2α), R^(3α), or R^(4α) must be carboxy.
 14. The compound of claim 13or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), and R^(6α) are independently selected from thegroup consisting of hydrogen and carboxy; R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino)propoxy, 2-(1-morpholino) ethoxy, CH₃O(CH₂)₂O(CH₂)₂—,

and

wherein one of R^(4β), R^(5β) or R^(6β) must be selected from the groupconsisting of thiophen-2-yl, thiophen-3-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol-2-yl, pyrrol-3-yl,1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl,N-Boc-indol-3-yl, N-Boc-pyrrol-2-yl, and N-Boc-pyrrol-3-yl; with theproviso that at least one of R^(2α), R^(3α), or R^(4α) must be carboxy.15. The compound of claim 14 or its pharmaceutically acceptable salt orester, wherein: R^(2α), R^(3α), R^(4α), R⁵, and R^(6α) are independentlyselected from the group consisting of hydrogen and carboxy; R^(2β),R^(3β), R^(4β), R^(5β) and R^(6β) are independently selected from thegroup consisting of hydrogen, methoxy, 3-(1-morpholino) propoxy,2-(1-morpholino) ethoxy, and CH₃O(CH₂)₂O(CH₂)₂; wherein one of R^(4β),R^(5β) or R^(6β) must be selected from the group consisting ofthiophen-2-yl, benzo[b]thiophen-2-yl, indol-2-yl, 1-methyl-indol-2-yl,N-Boc-indol-2-yl, N-Boc-pyrrol-2′yl, and N-Boc-pyrrol-3-yl; with theproviso that at least one of R^(2α), R^(3α), or R^(4α) must be carboxy.16. The compound of claim 15 selected from the group consisting of:4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;4-[3E-(4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(4-Thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid; 4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid, sodium salt; 4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzoicacid; 4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid,sodium salt; 4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoicacid; 4-[3-(2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoicacid; 4-[3E-(4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid; 4-[3E-{4-Fluoro-3-(thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid;4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicAcid; 4-[3E-(2-Fluoro-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(2,4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-{3E-[5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid; 4-[3E-(4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;2-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-indole-1-carboxylicacid tert-butyl ester;4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-{3E-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid; 4-[3E-(2,4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-{3E-[2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoicacid; 4-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(3-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid; 4-[3E-(2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-[3E-(2,4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid;4-{3E-[4-(1-Carboxy-1-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid; 2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicacid;4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid;5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylicacid methyl ester;5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylicacid;4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid; 4-[3E-(2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoicacid;4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid, sodium salt;2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1-carboxylicacid tert-butyl ester;4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid;4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-S-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride; 24-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid; 4-[3E-(2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid;4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride;4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride;4-[3E-(2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-[3E-(4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoicacid;4-{3E-[5-(1H-Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid;4-[3E-(2-Carbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoicacid;4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid;4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicacid, hydrochloride;4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid;4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoicacid;4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid;2-{4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-methyl-propionicacid;4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid, hydrochloride;4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoicacid;4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzoicacid; and4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoicacid ethyl ester, or its pharmaceutically acceptable salt or ester. 17.The compound of claim 16 selected from the group consisting of:4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicAcid; and4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride, or its pharmaceutically acceptable salt or ester.18. The compound of claim 17 wherein the compound is4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acidor its pharmaceutically acceptable salt or ester.
 19. The compound ofclaim 17 wherein the compound is4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid, orits pharmaceutically acceptable salt or ester.
 20. The compound of claim17 wherein the compound is4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoicAcid; and, or its pharmaceutically acceptable salt or ester.
 21. Thecompound of claim 17 wherein the compound is4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoicacid, hydrochloride, or its pharmaceutically acceptable salt or ester.22. The compound of claim 5 or its pharmaceutically acceptable salt orester, wherein: R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) areindependently selected from the group consisting of hydrogen andcarboxy; R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independentlyselected from the group consisting of hydrogen, halogen, heteroaryl,heterocyclic, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-lower alkyl, heteroaryllower alkoxy, and heterocyclic lower alkoxy, all of which can beoptionally substituted by one or more selected from the group consistingof hydroxy, hydroxyalkyl, —NR⁷R⁸, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R² islower alkyl; R⁷ and R⁸ are independently alkyl, and linked togetherforming a 6-membered monocyclic or benzofused ring; wherein one ofR^(4β), R^(5β) or R^(6β) must be a carbon-carbon linked heterocyclic;with the proviso that at least one of R^(2α), R^(3α), or R^(4α) must becarboxy.
 23. The compound of claim 22 or its pharmaceutically acceptablesalt or ester, wherein: R^(2α), R^(3α), R^(4α), R^(5α), and R^(6α) areindependently selected from the group consisting of hydrogen andcarboxy; R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) are independentlyselected from the group consisting of hydrogen, fluorine, chlorine,methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino)ethoxy, CH₃O(CH₂)₂O(CH₂)₂—,

and

wherein one of R^(4β), R^(5β) or R^(6β) must be a carbon-carbon linkedtetrahydrofuran-2-yl or dihydrofuran-2-yl; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be carboxy.
 24. The compoundof claim 5 or its pharmaceutically acceptable salt or ester, wherein:R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β)and R^(6β) are independently selected from the group consisting ofhydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl,carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic loweralkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl,aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lowerthioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lowerthioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl,arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —C(O)R²,R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl,heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl,hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,—(O(CH₂)₂)₁₋₃—O-lower alkyl, polyoxyalkylene, cycloalkyloxy,cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R¹)₂C(O)OH,—OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino,cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR²,—C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R²; whereinall R¹, R², R⁷ and R⁸ substituents can be optionally substituted withone or more selected from the group consisting of halo, alkyl, loweralkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.
 25. The compound of claim 5or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R¹)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of thiol, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸; wherein all R¹,R², R⁷ and R⁸ substituents can be optionally substituted with one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂.
 26. The compound of claim 5or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²) 2, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R¹)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α) R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R² R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R²)₂.
 27. The compound of claim 5or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R² R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R¹)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso that atleast one of R^(2α), R^(3α), or R^(4α) must be selected from the groupconsisting of —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂,—OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸; wherein all R¹,R², R⁷ and R⁸ substituents can be optionally substituted with one ormore selected from the group consisting of halo, alkyl, lower alkyl,alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.
 28. The compound of claim 3or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R², R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)₂C(O)OR², —NHC(O)R²,—N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R¹)₂, —C(O)NR⁷R⁸,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso thatR^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together, or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a heterocyclic or heteroaryl optionally substituted by one or morealkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl andoptionally substituted with one or more selected from the groupconsisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl,amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —NR⁷R⁸, and halo; andwith the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²)₂, —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R²)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R²)₂C(O)OH,—NHC(R¹)₂C(O)OR², —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂; wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂.
 29. The compound of claim 3or its pharmaceutically acceptable salt or ester, wherein: R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently selected from the group consisting of hydrogen,halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lowerthioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl,heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyllower alkyl, arylsulfonyl lower alkyl, —C(O)R² R²C(O)alkyl, aminoalkyl,cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino loweralkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol,carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —(O(CH₂)₂)₁₋₃—O-loweralkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy,aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl loweralkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,—OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)₂C(O)NHR²,—OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino,dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —NHR²,N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R²)₂C(O)OR, —NHC(O)R²)₂,—N(R¹)C(O)R², —NHC(O)OR², —NHC(O)SR², —NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸,—N(C(O)NHR²)₂, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂,thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio,arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH,—SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R²,—SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, sulfonic acid,sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl,carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷⁸R²,—C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸,—C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷R⁸,—C(CH₃)₂C(O)OH, —(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6,—PO₂H₂, —PO₃H₂, —P(R²)O₂H, and phosphate, all of which can be optionallysubstituted by one or more selected from the group consisting of halo,alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R¹ isindependently selected from the group consisting of hydrogen, loweralkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may beoptionally substituted by one or more selected from the group consistingof halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; R² is independently selected from the group consisting ofalkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl,heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, andheterocyclicalkyl, wherein all may be substituted by one or moreselected from the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂; R⁷ and R⁸ are independentlyselected from the group consisting of alkyl, alkenyl and aryl and linkedtogether forming a 4- to 12-membered monocyclic, bicylic, tricyclic orbenzofused ring; wherein one of R^(4β), R^(5β) or R^(6β) must be acarbon-carbon linked heterocyclic or heteroaryl, and only one of R^(2α),R^(3α), R^(4α), R^(5α) or R^(6α) can be —OCH₃; with the proviso thatR^(2α) and R^(3α) taken together or R^(3α) and R^(4α) taken together orR^(4α) and R^(5α) taken together or R^(2β) and R^(3β) taken together orR^(3β) and R^(4β) taken together or R^(4β) and R^(5β) taken togetherform a 5- or 6-membered ring containing one nitrogen, which mayoptionally be substituted with one or more selected from the groupconsisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy,hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR⁷R⁸, alkoxy, oxo,cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and—C(O)N(R²)₂; provided that R^(2α), R^(3α), R^(4α), R^(5α), R^(6α),R^(2β), R^(3β), R^(4β), R^(5β) and R^(6β) cannot be —OC(R¹)₂C(O)OH; andwith the proviso that at least one of R^(2α), R^(3α), or R^(4α) must beselected from the group consisting of cyano, tetrazol-5-yl, carboxy,—C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)NHR²,—C(O)NHC(O)N(R²)₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²),—C(O)NHSO₂NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHSO₂R², —C(CH₃)₂C(O)OH,—(CH₂)_(y)C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol,—SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂,—SO₂NHR₂, —SO₂N(R¹)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR²,—SO₂NHC(O)N(R¹)₂, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR²,—OC(R¹)₂C(O)NH₂, —OC(R²)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂,—OC(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R²)₂C(O)OH,—NHC(R¹)₂C(O)OR, —NHC(O)R², —N(R²)C(O)R², —NHC(O)OR², —NHC(O)SR²,—NHSO₂NHR², —NHSO₂R², —NHSO₂NR⁷R⁸, —N(C(O)NHR²)₂, —NR²SO₂R²,—NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂, wherein all R¹, R², R⁷ andR⁸ substituents can be optionally substituted with one or more selectedfrom the group consisting of halo, alkyl, lower alkyl, alkenyl,cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,aminoalkyl, —NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, —C(O)NR⁷R⁸, and C(O)N(R¹)₂.
 30. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 together with one or more pharmaceutically acceptablecarrier.
 31. A method for the treatment or prophylaxis of aninflammatory disorder, comprising administering an effective amount of acompound of claim
 1. 32. The method of claim 31, wherein the disorder isarthritis.
 33. The method of claim 31, wherein the disorder isrheumatoid arthritis.
 34. The method of claim 31, wherein the disorderis asthma.
 35. The method of claim 31, wherein the treatment is diseasemodifying for the treatment of rheumatoid arthritis.
 36. The method ofclaim 31, wherein the disorder is allergic rhinitis.
 37. The method ofclaim 31, wherein the disorder is chronic obstructive pulmonary disease.38. The method of claim 31, wherein the disorder is atherosclerosis. 39.The method of claim 31, wherein the disorder is restinosis.
 40. A methodfor inhibiting the expression of VCAM-1, comprising administering aneffective amount of a compound of claim 1.